Carbozamides with antifungal activity

ABSTRACT

Compounds of general formula I and their salts and solvates are antifungal agents and as such are useful in the treatment of various fungal infections. Pharmaceutical compositions including these compounds and processes for their preparation are also provided.

FIELD OF THE INVENTION

The present invention relates to a new series of carboxamides of generalformula I having potent antifungal activity. The invention also relatesto a process for their preparation, to pharmaceutical compositionscontaining them and to their use for the treatment of fungal diseases.

DESCRIPTION OF THE PRIOR ART

The compounds of the present invention are antifungal agents belongingto the azole class, whose mechanism of action is based on the inhibitionof the biosynthesis of ergosterol, the main sterol present in fungimembranes.

Other antifungal agents having this mechanism of action have beenreported in the literature. Patent applications EP 332387 and EP 617031describe azole derivatives containing an arylcarboxamide group. Thecompounds of the present invention are not only more potent antifungalagents than the compounds described in the above two patents but theyalso have a broader spectrum of antifungal activity since, unlike thecompounds described therein, they are also effective against filamentousfungi, including aspergillus.

DESCRIPTION OF THE INVENTION

The present invention relates to new carboxamides of general formula I##STR2## as racemates, diastereomer mixtures or as pure enantiomers,wherein: X represents N or CH;

Ar represents phenyl or phenyl substituted with one or more halogenand/or trifluoromethyl groups;

R₁ is C₁ -C₄ alkyl;

R₂ is hydrogen or C₁ -C₄ alkyl;

or R₁ together with R₂ form a C₂ -C₄ polymethylene chain;

R₃ is hydrogen, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkyl-C₁-C₄ alkyl, C₁ -C₄ haloalkyl, phenyl-C₁ -C₄ alkyl (wherein the phenylgroup can be optionally substituted with 1, 2, 3 or 4 groups R₅, whichcan be the same or different), a group --(CH₂)_(n) --CH₂ OH, a group--(CH₂)_(n) --CH₂ OBn, a group --(CH₂)_(n) --CH₂ NR₆ R₇, a group--(CH₂)_(n) --CH₂ COOR₆, or a group --(CH₂)_(n) --CH₂ COOB_(n), in whichcase R₄ is hydrogen;

or R₃ together with R₄ and the remainder of said compound of formula Iform an oxazolidine ring of formula I' ##STR3## or R₃ together with R₄and the remainder of said compound of formula I form a morpholine ringof formula I" ##STR4## wherein D is O, in which case the dotted linerepresents a covalent bond, or D is hydroxy or hydrogen, in which casethe dotted line is absent;

A represents phenyl or a monocyclic or bicyclic heterocyclic groupcontaining from 1 to 4 heteroatoms selected from N, O and S and witheach ring in the heterocyclic group being formed of 5 or 6 atoms,wherein A can be unsubstituted or have 1, 2, 3 or 4 groups R₈ ;

B represents a phenyl group which can be optionally substituted with 1,2, 3 or 4 groups R₉, or B represents a monocyclic or bicyclicheterocyclic group containing from 1 to 4 heteroatoms selected from N, Oand S and with each ring in the heterocyclic group being formed of 5 or6 atoms, which can be optionally substituted with 1, 2, 3 or 4 groups R₉;

R₅ represents C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or halogen;

n represents 0, 1, 2 or 3;

R₆ and R₇ independently represent hydrogen or C₁ -C₄ alkyl;

R₈ represents C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄ haloalkyl, C₁ -C₄alkoxy, C₁ -C₄ haloalkoxy, halogen, phenyl (optionally substituted witha group halogen, cyano, C₁ -C₄ haloalkyl or C₁ -C₄ haloalkoxy), nitro,cyano, hydroxy, hydroxymethyl, a group --NR₆ R₇, a group --CONR₆ R₇, agroup --COR₆, a group --COOR₆, or a group --SO_(z) R₁₀ ;

R₉ represents C₁ -C₄ alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, C₃ -C₆cycloalkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy,2-carboxy-2-propyl, halogen, nitro, cyano, hydroxy, benzyloxy,hydroxymethyl, a group --CH₂ --OCO--R₆, a group --CO--R₆, a group--COO--R₆, a group --SO_(z) R₁₀, a group --NR₆ R₇, a group --CONR₆ R₇, agroup --C(═NR₆)NHR₁₁, a group --C(═NR₁₁)OR₆, and additionally one of thegroups R₉ can also represent 1-pyrrolyl, 1-imidazolyl,1H-1,2,4-triazol-1-yl, 5-tetrazolyl (optionally substituted with C₁ -C₄alkyl), 1-pyrrolidinyl, 4-morpholinyl, 4-morpholinyl-N-oxide, phenyl orphenoxy (both optionally substituted with a group C₁ -C₄ alkyl, C₁ -C₄haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy, halogen, nitro or cyano),or a group of formula (i)-(iv) ##STR5## R₁₀ represents C₁ -C₄ alkyl; zrepresents 0, 1 or 2;

R₁ represents hydrogen, --CONH₂, --COMe, --CN, --SO₂ NHR₆, --SO₂ R₁₀,--OR₆, or --OCOR₆ ;

R₁₂ represents hydrogen or methyl;

R₁₃ represents hydrogen, isopropyl, cyclopentyl, cyclopropyl, 2-butyl,3-pentyl, 3-hydroxy-2-butyl, or 2-hydroxy-3-pentyl;

p represents 0 or 1;

R₁₄ represents halogen, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, nitro,amino, cyano, or a group of formula (i);

E represents --CH₂ -- or --C(═O)--;

G represents NH or O;

Y represents a single bond, --S--, --SO--, --SO₂ --, --O-- or --NR₆ --;

m and q independently represent 0, 1 or 2; and the salts and solvatesthereof.

The invention also provides a pharmaceutical composition which comprisesan effective amount of a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof in admixture with one or morepharmaceutically acceptable excipients.

The invention further provides the use of a compound of formula I or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament for the treatment or prophylaxis of fungal infections inanimals, including human beings.

The invention further provides the use of a compound of formula I or apharmaceutically acceptable salt or solvate thereof for the treatment orprophylaxis of fungal infections in animals, including human beings.

The invention also provides a method of treating or preventing fungalinfections in animals, including human beings, which method comprisesadministering to a patient in need thereof an effective amount of acompound of formula I or a pharmaceutically acceptable salt or solvatethereof.

In addition to being useful for the treatment of fungal infections inanimals, the compounds of the present invention possess antifungalproperties which can be useful for combatting or preventing plant fungalinfections. The invention thus provides the use of a compound of formulaI or a salt or solvate thereof for the treatment or prophylaxis offungal infections in plants.

The invention still further provides an agrochemical composition whichcomprises an effective amount of a compound of formula I or a salt orsolvate thereof in admixture with one or more agrochemically acceptableexcipients.

The invention also provides a process for preparing a compound offormula I, which comprises:

(a) reacting a compound of formula II ##STR6## wherein X, R₁, R₂, R₃, R₄and Ar are as defined above, with an acid of formula III ##STR7##wherein A, B, Y, m and q are as defined above, in the presence of acondensing agent, or with a reactive derivative of said acid III such asthe acid chloride, the anhydride or the mixed anhydride in the presenceof a proton scavenger base; or

(b) converting in one or a plurality of steps a compound of formula Iinto another compound of formula I; and

(c) if desired, after steps (a) or (b), reacting a compound of formula Iwith an acid to give the corresponding acid addition salt.

In the above definitions, the term C₁ -C₄ alkyl, as a group or part of agroup, means a linear or branched alkyl chain containing from 1 to 4carbon atoms. Therefore, it includes methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, and tert-butyl.

A C₂ -C₄ alkenyl group means a linear or branched alkyl chain containingfrom 2 to 4 carbon atoms and additionally containing one or more doublebonds. Examples include ethenyl, 1-propenyl, 2-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, and 1,3-butadienyl.

A C₂ -C₄ alkynyl group means a linear or branched alkyl chain containingfrom 2 to 4 carbon atoms and additionally containing one or more triplebonds. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, and 3-butynyl.

A C₂ -C₄ polymethylene chain means ethylene, propylene or butylene.

A C₁ -C₄ haloalkyl group means a group resulting from the substitutionof one or more hydrogen atoms of a C₁ -C₄ alkyl group by one or morehalogen atoms (i.e. fluorine, chlorine, bromine or iodine), which can bethe same or different. Examples include trifluoromethyl,trichloromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl,difluoromethyl, dichloromethyl, 2-chloroethyl, 2,2-dichloroethyl,2,2,2-trichloroethyl, pentachloroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,3-chloropropyl, 3,3-dichloropropyl, 3,3,3-trichloropropyl,2,2,3,3,3-pentachloropropyl, 3-fluoropropyl, 3,3-difluoropropyl,3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl,2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-chlorobutyl,4-fluorobutyl, 4-iodobutyl and 4-bromobutyl.

The term C₃ -C₆ cycloalkyl, as a group or part of a group, representscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The abbreviation Bn represents benzyl.

A C₁ -C₄ alkoxy group means a group derived from the union of a C₁ -C₄alkyl group to an oxygen atom of an ether functional group. Examplesinclude methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy and tert-butoxy.

A C₁ -C₄ haloalkoxy group means a group resulting from the substitutionof one or more hydrogen atoms of a C₁ -C₄ alkoxy group by one or morehalogen atoms, which can be the same or different. Examples includetrifluoromethoxy, fluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy,2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy,2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy,heptafluoropropoxy, 4-fluorobutoxy, and 4-chlorobutoxy.

In the compounds of the present invention Ar represents a phenyl groupor a phenyl group substituted with one or more halogen and/ortrifluoromethyl groups. The halogen atoms may be fluorine, chlorine,bromine or iodine atoms, of which fluorine and chlorine atoms arepreferred. There may be one or more such substituents on the phenylgroup, and where there are more than one, these may be the same ordifferent. When the phenyl group is substituted, the substituents can beon any available position of the phenyl ring, but they are preferably onthe 2- and/or 4-positions. Examples of substituted phenyl groups include4-(trifluoromethyl)phenyl, 2-fluorophenyl, 4-fluorophenyl,2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-bromophenyl,2-fluoro-4-iodophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,4-chlorophenyl and 2-fluoro-4-(trifluoromethyl)phenyl, of which2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl and4-chlorophenyl are preferred, and 2-fluorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 4-(trifluoromethyl)phenyl and 4-chlorophenyl aremore preferred.

In the compounds of the present invention R₁ represents a C₁ -C₄ alkylgroup, or together with R₂ forms a C₂ -C₄ polymethylene chain, butpreferably R₁ is C₁ -C₄ alkyl, and more preferably R₁ is methyl.

In the compounds where R₂ is hydrogen or C₁ -C₄ alkyl, or together withR₁ forms a C₂ -C₄ polymethylene chain, those wherein R₂ is hydrogen ormethyl are preferred, and those wherein R₂ is hydrogen are morepreferred.

From among the compounds wherein R₃ and R₄ are unconnected or can bebonded together forming an oxazolidine or morpholine ring, those whereinR₃ and R₄ are unconnected (i.e. R₄ represents hydrogen) are preferred,and those wherein both R₃ and R₄ represent hydrogen are more preferred.

In the compounds of the present invention, the groups A and B representphenyl or a monocyclic or bicyclic heterocyclic group, wherein each ringin the heterocyclic group is formed of 5 or 6 atoms and wherein from 1to 4 of the ring atoms forming said heterocyclic group are heteroatomsselected from the group consisting of N, O and S. Both A and B can beunsubstituted or have 1, 2, 3 or 4 substituents R₈ or R₉ respectively,which can be on any available position of any of the rings. When thereis more than one substituents on ring A or B, they can be the same ordifferent, provided that, as mentioned above, for certain meanings of R₉there cannot be more than one such group on ring B. Examples ofmonocyclic heterocyclic groups A or B include thiophene, furan, pyran,pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole,1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole,1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, furazan,pyrroline, imidazoline and pyrazoline. Examples of bicyclic heterocyclicgroups A or B include among others benzimidazole, benzofuran,isobenzofuran, benzofurazan, indole, isoindole, indolizine, indazole,benzothiophene, benzothiazole, quinoline, isoquinoline, phtalazine,quinazoline, quinoxaline, cinnoline, imidazopyridine, imidazopyrimidine,imidazopyrazine, imidazopyridazine, pyrazolopyrazine, pyrazolopyridineand pyrazolopyrimidine.

Among all the possible meanings for A those wherein A represents phenylor a 5- or 6-membered heterocyclic ring containing from 1 to 3heteroatoms selected from N, O and S are preferred; those groups whereinA represents a 5- or 6-membered aromatic heterocyclic ring containingfrom 1 to 3 heteroatoms selected from N, O and S are more preferred;those wherein A represents a thiophene, furan, pyrrole, imidazole,pyrazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, or1,2,4-thiadiazole ring are still more preferred; and those wherein Arepresents thiophene, thiazole or pyrazole are particularly preferred.All these groups A can be unsubstituted or have 1, 2, 3 or 4, preferably1 or 2, groups R₈. As preferred meanings for R₈ we can mention C₁ -C₄alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, halogen and amino, of whichC₁ -C₄ alkyl and C₁ -C₄ haloalkyl are more preferred.

As for B, those groups wherein B represents a phenyl group optionallysubstituted with 1, 2, 3 or 4 substituents R₉ are preferred. As examplesof substituted phenyl rings we can mention among others 2-methylphenyl,4-methylphenyl, 4-tert-butylphenyl, 4-(2-carboxy-2-propyl)phenyl,4-vinylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,4-iodophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,6-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl,2,3,5,6-tetrafluorophenyl, 2-(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,4-(trichloromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl,4-(difluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl,4-(2-fluoroethoxy)phenyl, 4-(2,2-difluoroethoxy)phenyl,4-(2,2,2-trifluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl,3-nitrophenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 4-(4-cyanophenyl)phenyl,4-(4-cyanophenoxy)phenyl, 2-methyl-4-cyanophenyl,2-chloro-4-cyanophenyl, 2-cyano-4-(trifluoromethyl)phenyl,4-(methoxycarbonyl)phenyl, 2-methoxy-4-(trifluoromethyl)phenyl,2-fluoro-4-(ethoxycarbonyl)phenyl, 4-(methylthio)phenyl,4-(methylsulfinyl)phenyl, 4-(methylsulfonyl)phenyl, 4-aminophenyl,4-dimethylaminophenyl and 4-carbamoylphenyl. More preferred meanings forB are those wherein B represents phenyl substituted with 1 or 2 groupsR₉, of which those wherein one of the substituents R₉ is in the paraposition are still more preferred. Preferred meanings for R₉ include C₁-C₄ alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, C₃ -C₆ cycloalkyl, C₁ -C₄haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy, 2-carboxy-2-propyl,halogen, nitro, cyano, hydroxy, benzyloxy, hydroxymethyl, a group --CH₂--OCO--R₆, a group --CO--R₆, a group --COO--R₆, a group --SO_(z) R₁₀, agroup --NR₆ R₇, a group --CONR₆ R₇, a group --C(═NR₆)NHR₁₁ or a group--C(═NR₁₁)OR₆.

In the compounds wherein Y represents a single bond, --S--, --SO--,--SO₂ --, --O-- or --NR₆ -- and m and q independently represent 0, 1 or2, those wherein Y represents a single bond and m═q═0, that is, thosewherein ring B is directly bonded to ring A through a covalent bond arepreferred.

Preferred compounds of the present invention include those in which,independently or in any compatible combination:

X represents N;

R₁ represents C₁ -C₄ alkyl;

R₂ represents hydrogen;

R₄ represents hydrogen;

Ar represents 2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or4-chlorophenyl;

A represents phenyl or a 5- or 6-membered heterocyclic ring containingfrom 1 to 3 heteroatoms selected from N, O and S, wherein A can beunsubstituted or have 1, 2, 3 or 4 groups R₈ ;

B represents a phenyl group which can be optionally substituted with 1,2, 3 or 4 substituents R₉ ;

the stereochemistry of the compounds is (R,R).

Particularly preferred compounds of the present invention include thosein which, independently or in any compatible combination:

X represents N;

R₁ represents methyl;

R₂ represents hydrogen;

R₃ represents hydrogen;

R₄ represents hydrogen;

Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,4-(trifluoromethyl)phenyl or 4-chlorophenyl;

A represents a 5- or 6-membered aromatic heterocyclic ring containingfrom 1 to 3 heteroatoms selected from N, O and S, and which can beunsubstituted or have 1 or 2 groups R₈ ;

B represents a phenyl group substituted with 1 or 2 groups R₉ ;

Y represents a single bond and m═q═0;

the stereochemistry of the compounds is (R,R).

Accordingly, a preferred class of compounds of formula I is thatwherein:

X represents N;

R₁ represents C₁ -C₄ alkyl;

R₂ represents hydrogen;

R₄ represents hydrogen;

Ar represents 2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or4-chlorophenyl;

A represents phenyl or a 5- or 6-membered heterocyclic ring containingfrom 1 to 3 heteroatoms selected from N, O and S, wherein A can beunsubstituted or have 1, 2, 3 or 4 groups R₈ ;

B represents a phenyl group which can be optionally substituted with 1,2, 3 or 4 substituents R₉ ; and

the stereochemistry of the compounds is (R,R).

A more preferred class of compounds of formula I is that wherein:

X represents N;

R₁ represents methyl;

R₂ represents hydrogen;

R₃ represents hydrogen;

R₄ represents hydrogen;

Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,4-(trifluoromethyl)phenyl or 4-chlorophenyl;

A represents a 5- or 6-membered aromatic heterocyclic ring containingfrom 1 to 3 heteroatoms selected from N, O and S, and which can beunsubstituted or have 1 or 2 groups R₈ ;

B represents a phenyl group substituted with 1 or 2 groups R₉ ;

Y represents a single bond and m═q═0; and

the stereochemistry of the compounds is (R,R).

A particularly preferred class of compounds of formula I is thatwherein:

X represents N;

R₁ represents methyl;

R₂ represents hydrogen;

R₃ represents hydrogen;

R₄ represents hydrogen;

Ar represents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,4-(trifluoromethyl)phenyl or 4-chlorophenyl;

A represents thiophene, furan, pyrrole, imidazole, pyrazole, thiazole,isothiazole, oxazole, isoxazole, 1,2,4-triazole, 1,3,4-oxadiazole,1,3,4-thiadiazole, 1,2,4-oxadiazole, or 1,2,4-thiadiazole, wherein A canbe optionally substituted with one or two C₁ -C₄ alkyl or C₁ -C₄haloalkyl groups;

B represents a phenyl group substituted with 1 or 2 groups R₉ ;

R₉ represents C₁ -C₄ alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, C₃ -C₆cycloalkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy,2-carboxy-2-propyl, halogen, nitro, cyano, hydroxy, benzyloxy,hydroxymethyl, a group --CH₂ --OCO--R₆, a group --CO--R₆, a group--COO--R₆, a group --SO_(z) R₁₀, a group --NR₆ R₇, a group --CONR₆ R₇, agroup --C(═NR₆)NHR₁₁ or a group --C(═NR₁₁)OR₆ ;

Y represents a single bond and m═q═0; and

the stereochemistry of the compounds is (R,R).

The compounds of formula I contain one or more basic nitrogen atoms and,consequently, they can form salts with acids, which are also included inthe present invention. There is no limitation on the nature of thesesalts, provided that, when used for therapeutic purposes, they arepharmaceutically acceptable, which, as is well-known in the art, meansthat they do not have reduced activity (or unacceptable reducedactivity) or increased toxicity (or unacceptable increased toxicity)compared with the free compounds. Examples of these salts include: saltswith an inorganic acid such as hydrochloric acid, hydrobromic acid,hydriodic acid, nitric acid, perchloric acid, sulfuric acid orphosphoric acid; and salts with an organic acid, such as methanesulfonicacid, trifluoromethanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid,maleic acid; and other mineral and carboxylic acids well known to thoseskilled in the art. The salts are prepared by reacting the free basewith a sufficient amount of the desired acid to produce a salt in theconventional manner. Free bases and their salts differ in certainphysical properties, such as solubility, but they are equivalent for thepurposes of the invention.

Some compounds of the present invention can exist in solvated form,including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for the purposes of theinvention.

The compounds of formula I contain one or more asymmetric carbons and,consequently, can exist as different stereoisomers. The presentinvention covers both each of the individual stereoisomers and theirmixtures. When R₁ is C₁ -C₄ alkyl and R₂ is hydrogen, those compounds offormula I wherein the absolute configuration of the carbon atoms towhich the Ar and R₁ groups are bonded is (R,R) are preferred, i.e.compounds of formula: ##STR8##

Diastereoisomers can be separated by conventional techniques such aschromatography or fractional crystallization. The optical isomers can beresolved using any of the conventional techniques of optical resolutionto give optically pure isomers. Such a resolution can be performed inany chiral synthetic intermediate as well as in the products of generalformula I. The optically pure isomers can also be individually obtainedusing enantiospecific synthesis. We have obtained the optically pure(R,R) isomers starting from optically pure amine II, prepared followingthe general procedure described in J.Org.Chem, 1995, 60, 3000-3012. Asstated above, the present invention covers the individual isomers aswell as their mixtures (e.g. racemic mixtures), whether as obtained bysynthesis or by physically mixing them up.

Some of the compounds of formula I may present tautomerism. For example,when the compounds of the present invention contain an amidino group offormula --C(═NR₆)NHR₁₁, the following tautomeric structures may exist inequilibrium: ##STR9## all of which are encompassed by the presentinvention.

The compounds of formula I can be prepared using the proceduresdescribed below. The precise method used for the preparation of a givencompound may vary depending on its chemical structure.

The compounds of formula I can be prepared by reacting an amine offormula II with an acid of formula III in the presence of an appropriatecondensing agent, for example dicyclohexylcarbodiimide, alone or incombination with 1-hydroxybenzotriazole, in a polar solvent, such as asubstituted amide (for example N-methylpyrrolidone ordimethylformamide), an ether (for example tetrahydrofuran or dioxane) ordiglyme, at a temperature preferably comprised between 0° C. and 100° C.Alternatively, compounds of formula I can be prepared by reacting anamine II with a reactive derivative of an acid III, such as the acidchloride, anhydride or mixed anhydride. The reaction is carried out inthe presence of a proton scavenger base, such as triethylamine orpyridine, in a suitable solvent such as dichloromethane or chloroform.

Alternatively, compounds of formula I wherein Y represents --O--, --S--or --NR₆ -- and m is 0 can be prepared from the corresponding compoundwherein A is substituted with a halogen atom, for example bromine,instead of a group --Y(CH₂)_(q) --B by treatment with an alkaline metalsalt of the corresponding alcohol or thiol of formula HY(CH₂)_(q) --B,for example the sodium salt, or by treatment with an amine of formulaHNR₆ (CH₂)_(q) --B in a suitable aprotic solvent such asN-methylpyrrolidone at a temperature between room temperature and thatof the refluxing solvent.

Moreover, some compounds of formula I can also be prepared byinterconversion from another compound of formula I in one or a pluralityof steps using reactions well known in organic chemistry, such as thereactions listed below. These reactions are mentioned here only asillustrative examples of the several procedures which can be used tointerconvert compounds of the present invention and are not intended tolimit the scope of the preparation of compounds of formula I in any way.

Thus, for example, the compounds of formula I wherein R₃ together withR₄ and the remainder of said compound of formula I form a morpholinering of formula I", wherein D is hydrogen and the dotted line is absent,can be prepared from the corresponding compound of formula I wherein R₃=--(CH₂)₂ OH by treatment with diethylazadicarboxylate andtributylphosphine in a suitable solvent such as tetrahydrofuran. Thecompounds of formula I wherein R₃ together with R₄ and the remainder ofsaid compound of formula I form a morpholine ring of formula I", whereinD is hydroxy and the dotted line is absent, can be prepared from thecorresponding compound of formula I wherein R₃ =--(CH₂)₂ OH by oxidationfor example by treatment with activated DMSO and a base, such astriethylamine, in a suitable solvent, such as dichloromethane orchloroform. The compounds of formula I wherein R₃ together with R₄ andthe remainder of said compound of formula I form a morpholine ring offormula I", wherein D is O and the dotted line represents a covalentbond, can be prepared from the corresponding compound of formula Iwherein R₃ =--CH₂ COOH using a suitable dehydrating agent oralternatively they can be prepared from the corresponding compound offormula I wherein R₃ =--(CH₂)₂ OH by overoxidation.

Furthermore, it is also possible to convert a group R₃ in a compound offormula I into another group R₃ using standard methods of organicsynthesis. Thus, a benzyl ether can be converted to the correspondingalcohol by hydrogenation in the presence of a suitable catalyst such asPd/C in a suitable solvent such as an alcohol at a hydrogen pressurebetween 1 and 5 atm. An ester group can be hydrolized to thecorresponding acid using conventional procedures; in case of benzylesters, this conversion can be carried out by hydrogenation in the sameexperimental conditions mentioned above. An ester group can also bereduced by treatment with a suitable metal hydride such as sodiumborohydride in a suitable solvent such as ethanol to give thecorresponding alcohol.

It is also possible to use a group B in a compound of formula I togenerate other groups B thus giving rise to other compounds of formulaI. For example, a nitro group can be reduced to an amino group, forexample by hydrogenation in the presence of a catalyst such as Pd/C in asuitable solvent such as an alcohol, for example ethanol, at atemperature between room temperature and that of the refluxing solventand at a pressure preferably between atmospheric pressure and 10 atm. Athioether group can be oxidized to a sulfinyl or sulfonyl group bytreatment with a suitable oxidising agent. For example, a thioethergroup can be oxidized to a sulfonyl group by treatment withm-chloroperbenzoic acid in a suitable solvent such as a halogenatedhydrocarbon at a temperature preferably between 0° C. and roomtemperature. Moreover, an amino group can be converted to a group offormula (i) by treatment with phenyl chloroformate, subsequent reactionof the phenyl carbamate thus obtained with hydrazine and finallycyclisation of the resulting semicarbazide with formamidine oracetamidine in a suitable solvent such as dimethylformamide at atemperature between room temperature and that of the refluxing solvent.A nitrile group can be converted to a tetrazole group by treatment witha suitable azide such as sodium azide or ammonium azide (which may beprepared in situ from sodium azide and ammonium chloride) in a suitablesolvent such as a polar solvent, for example dimethylformamide orN-methylpyrrolidone, at a temperature preferably between roomtemperature and that of the refluxing solvent. Another example ofinterconversion is the N-alkylation of a group of formula (i) or atetrazole by treatment with the corresponding alkyl halide in thepresence of a base such as potassium or cesium carbonate in a suitableaprotic solvent such as dimethylformamide. A nitrile group can behydrolized to a carbamoyl group by treatment with ammonium hydroxide ina suitable solvent such as tetrahydrofuran-water mixtures under reflux.A nitrile group can also be converted to an alkyl imidate group bybubbling HCl gas in an alcohol, such as methanol. An alkyl imidate groupcan also be converted to an amino(imino)methyl group by reaction with anamine using the corresponding alkanol as solvent. Moreover, a halogenatom, for example bromo or iodo, can be converted to a phenyl group by acoupling reaction between the corresponding haloderivative and a boronicacid or ester of formula (RO)₂ B-phenyl (wherein R represents hydrogenor C₁ -C₄ alkyl) in the presence of a palladium catalyst such asPd(OAc)₂ or Pd(PPh₃)₄ in a suitable solvent such as dimethoxyethane at atemperature preferably between room temperature and that of therefluxing solvent. A halogen atom, for example a fluorine atom, can beconverted into a C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy, phenoxy, --SR₁₀,triazole or imidazole group by treatment with an alkaline metal salt ofthe corresponding alcohol, thiol, triazole or imidazole, for example thesodium salt, in a suitable aprotic solvent such as N-methylpyrrolidoneat a temperature between room temperature and that of the refluxingsolvent; moreover, it can also be converted into an amine (--NR₆ R₇, 1-pyrrolidine, morpholine, a group of formula (ii) or a group of formula(iii)) by treatment with the corresponding amine in a suitable aproticsolvent such as N-methylpyrrolidone at a temperature between roomtemperature and that of the refluxing solvent.

Furthermore, a compound of formula I wherein Y represents --SO-- or--SO₂ -- can be prepared from the corresponding compound of formula Iwherein Y is --S-- by oxidation as described above in connection withgroup B.

As it will be apparent to those skilled in the art, theseinterconversion reactions can be carried out both on the final productsof formula I or on any synthetic intermediate thereof.

Amines of formula II can be prepared as described in J.Org.Chem, 1995,60, 3000-3012, EP 332387 or EP 617031.

Acids of formula III or derivatives thereof are commercially available,widely described in the literature or can be prepared by methodsanalogous to those known in the art. Thus, for example, 5-substituted1-arylpyrazole-4-carboxylic acids can be prepared by reacting thecorresponding arylhydrazine with the product obtained from reacting thecorresponding ethyl acylacetate with dimethylformamide dimethylacetal,followed by alkaline hydrolysis (KOH/EtOH--H₂ O), as described in J.Heterocyclic Chem. 1987, 24, 1669. 1-Arylpyrazole-4-carboxylic acids canbe prepared by reacting the corresponding arylhydrazine withcarbethoxymalonaldehyde, followed by alkaline hydrolysis, as describedin Gazz.Chim.Ital., 1946, 76, 56. 1-Aryl-5-aminopyrazole-4-carboxylicacids can be prepared by reacting ethyl ethoxymethylenecyanoacetate withthe corresponding arylhydrazine, followed by hydrolysis under basicconditions, as described in Helv.Chim.Acta, 1959, 349.2-Aryl-4-alkylthiazole-5-carboxylic acids can be prepared by reactingthe corresponding thiobenzamide with methyl acylchloroacetate in ethanolfollowed by alkaline hydrolysis, as described in Eur.J.Med.Chem. 1976,11, 567. 2-Arylthiazole-4-carboxylic acids can be prepared by reactingthe corrsponding thiobenzamide with ethyl bromopyruvate in ethanolfollowed by alkaline hydrolysis. 1-Arylpyrrole-3-carboxylic acids areprepared by reacting the correpsonding aniline with2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde in acetic acid underreflux, followed by oxidation with silver nitrate, as described inOrg.Prep.Proced.Int., 1995, 27, 236. 5-Arylthiophene-2-carboxylic acidscan be prepared by reacting the corresponding acetophenone,dimethylformamide and ethyl thioglycolate in the presence of POCl₃,followed by alkaline hydrolysis, as described in Tetrahedron Lett.,1968, 1317. 5-Aryl-3-aminothiophene-2-carboxylic acids can be preparedby reacting the corresponding β-chlorocinnamonitrile with ethylthioglycolate in the presence of a base, followed by alkalinehydrolysis, as described in Synthesis, 1984, 275.5-Aryl-1,3,4-oxadiazole-2-carboxylic acids can be prepared by thegeneral procedure described in J. Prakt.Chem. 1985, 327, 109.3-Aryl-1,2,4-oxadiazole-5-carboxylic acids can be prepared by thegeneral procedure described in J. Med. Chem. 1995, 38, 1355.5-Aryl-1,2,4-oxadiazole-3-carboxylic acids can be prepared by thegeneral procedure described in Bull. Chem.Soc.Jpn. 1985, 58, 2519.3-Aryl-1,2,4-thiadiazole-5-carboxylic acids and5-aryl-1,2,4-thiadiazole-3-carboxylic acids can be prepared by thegeneral procedure described in J. Org.Ciem. 1977, 42, 1813.

The present invention further provides compositions that contain acompound of the present invention, together with an excipient andoptionally other auxiliary agents, if necessary. The compounds of thepresent invention can be administered in different pharmaceuticalpreparations, the precise nature of which will depend, as it is wellknown, upon the chosen route of administration and the nature of thepathology to be treated.

Thus, solid compositions according to the present invention for oraladministration include compressed tablets, dispersible powders, granulesand capsules. In tablets, the active component is admixed with at leastone inert diluent such as lactose, starch, mannitol, microcrystallinecellulose or calcium phosphate; granulating and disintegrating agentsfor example corn starch, gelatine, microcrystalline cellulose orpolyvinylpyrrolidone; and lubricating agents for example magnesiumstearate, stearic acid or talc. The tablets may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and, thereby, provide a sustained action over alonger period. Gastric film-coated or enteric film-coated tablets can bemade with sugar, gelatin, hydroxypropylcellulose, or acrylic resins.Tablets with a sustained action may also be obtained using an excipientwhich provides regressive osmosis, such as the galacturonic acidpolymers. Formulations for oral use may also be presented as hardcapsules of absorbable material, such as gelatin, wherein the activeingredient is mixed with an inert solid diluent and lubricating agents,or pasty materials, such as ethoxylated saturated glycerides. Softgelatin capsules are also possible wherein the active ingredient ismixed with water or an oily medium, for example peanut oil, liquidparaffin or olive oil.

Dispersible powders and granules suitable for the preparation of asuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent; a suspending agent, suchas sodium carboxymethylcellulose, methylcellulose,hydroxypropyl-methylcellulose, sodium alginate, polyvinylpirrolidone,gum tragacanth, xantham gum, gum acacia, and one or more preservatives,such as methyl or n-propyl p-hydroxybenzoate. Additional excipients, forexample sweetening, flavoring and coloring agents may also be present.

Liquid compositions for oral administration include emulsions,solutions, suspensions, syrups and elixirs containing commonly usedinert diluents, such as distilled water, ethanol, sorbitol, glycerol, orpropylene glycol. Aqueous solutions can also be prepared usingβ-cyclodextrins, such as hydroxypropyl-β-cyclodextrin. Such compositionsmay also comprise adjuvants such as wetting agents, suspending agents,sweetening, flavoring, perfuming, preserving agents and buffers.

Other compositions for oral administration include spray compositions,which may be prepared by known methods. The spray compositions willcontain a suitable propellent.

Preparations for injection, according to the present invention, forparenteral administration include sterile aqueous or non-aqueoussolutions, suspensions or emulsions, in a non-toxicparentally-acceptable diluent or solvent. Examples of aqueous solventsor suspending media are distilled water for injection, Ringer'ssolution, and isotonic sodium chloride solution. Aqueous solutions canalso be prepared using β-cyclodextrins, such ashydroxypropyl-β-cyclodextrin. Examples of non-aqueous solvents orsuspending media are propylene glycol, polyethylene glycol, vegetableoils such as olive oil, or alcohols such as ethanol. These compositionsmay also include adjuvants such as wetting, preserving, emulsifying anddispersing agents. They may be sterilized by one of the known methods ormanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use. When all of the components are sterile, theinjectables will maintain the sterility if they are manufactured insterile environment.

Preparations for vaginal administration according to the presentinvention include tablets, capsules, softgels, moulded pessaries,creams, foams and vaginal douches. Vaginal tablets provide the activecomponent in admixture with lactose, microcrystalline cellulose,pregelatinized starch, polyvidone and magnesium stearate as typicalexcipients. Soft gelatin capsules (softgels) can be made dispersing theactive ingredient in an oily medium, for example liquid paraffin,dimethylpolysiloxane 1000 or hydrogenated soybean oil. Moulded pessariesprovide the active ingredient in admixture with a suitable synthetic orsemisynthetic base (such as Suppocire® or Novata® types). Low viscositysaturated C₈ to C₁₂ fatty acid glycerides and colloidal silice are alsoadded to improve incorporation and to prevent sedimentation of theactive ingredient. Vaginal creams can be prepared as emulsions, withsufficient viscosity to retain their integrity and adhere to the vaginalcavity. Neutral fats, fatty acids, waxes, mineral oils and fatty acidesters can be used as the oily phase. Water, glycerine, sorbitolsolution and polyethylene glycol are suitable excipients for the aqueousphase. Non-ionic emulsifying agents like polyethylene glycol ethers mayalso be used, and such compositions may also contain preserving,buffering and stiffening agents. Foaming systems can be made using afoamer (dispenser) that is able to transform a solution into a foam.Such systems may include cosolvents, buffers, preservatives, foamstabilizers and perfumes in an aqueous vehicle. Vaginal douches maycontain cosolvents, preservatives, buffers and perfuming agents in asurfactant rich aqueous solution.

A compound of the invention may also administered in the form ofsuppositories for rectal administration of the drug, or as creams,ointments, pastes, lotions, gels, sprays, foams, aerosols, solutions,suspensions or powders for topical use. Such compositions are preparedfollowing conventional procedures well known to those skilled in theart.

A compound of the invention may also be administered as a hair or bodyshampoo. These formulations may be prepared using suitable ionic and/oramphoteric surface-active agents such as sodium laureth sulfate,triethanolamine laureth sulfate, cocoamidopropyl betaine; thickeningagents for example cocamide DEA, carbomer, sodium chloride andpolyethylene glycol 6000 distearate; and optionally, emolient andsuperfatting agents, buffers, and preserving and perfuming agents.

The dosage and frequency of dose may vary depending upon the nature andseverity of the fungal disease, symptoms, age and body weight of thepatient, as well as upon the route of administration. In general, thecompounds of the invention will be administered orally or parenterallyat a dosage ranging from 0.01 mg/Kg/day to 100 mg/Kg/day, which can beadministered as a single dose or as divided doses.

Following are some representative preparations for tablets, capsules,syrups, aerosols and injectables. They can be prepared followingstandard procedures and they are useful in the treatment of fungaldiseases.

    ______________________________________    Tablets    Compound of formula I                        100        mg    Dibasic calcium phosphate                        125        mg    Sodium starch glycolate                        10         mg    Talc                12.5       mg    Magnesium stearate  2.5        mg                        250.0      mg    Hard gelatin capsules    Compound of formula I                        100        mg    Lactose             197        mg    Magnesium stearate  3          mg                        300        mg    Syrup    Compound of formula I                        0.4        g    Sucrose             45         g    Flavouring agent    0.2        g    Sweetening agent    0.1        g    Water to            100        mL    Aerosol    Compound of formla I                        4          g    Flavouring agent    0.2        g    Propylene glycol to 100        mL    Suitable propellent to                        1          unit    Injectable preparation 1    Compound of formula I                        100        mg    Benzylic alcohol    0.05       mL    Propylene glycol    1          mL    Water to            5          mL    Injectable preparation 2    Compound of formula I                        100        mg    Hydroxypropyl-β-cydodextrin                        1          g    Sodium chloride     90         mg    Water to            10         mL    ______________________________________

The following examples illustrate, but do not limit, the scope of thepresent invention:

REFERENCE EXAMPLE 1 1-(4-Chlorophenyl)-1H-pyrazole-4-carboxylic acid

(a) A solution of carbethoxymalonaldehyde (0.8 g, 5.55 mmol; obtainedaccording to Panizzi, L. Gazz.Chim.Ital., 1946, 76, 56) in ethanol (25mL) was treated with 4-chlorophenylhydrazine hydrochloride (1.0 g, 5.55mmol) at reflux for 5 h. The resulting reddish mixture was concentratedto an oil that was purified by flash chromatography to give ethyl1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate (0.68 g, 49%) as a whitesolid: mp 127°-128° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.37 (s, 1H,pyrazole), 8.09 (s, 1H, pyrazole), 7.67 (dt, J_(t) =2, J_(d) =9, 2H,arom), 7.44 (dt,J_(t) =2, J_(d) =9, 2H, arom), 4.35 (q, J=7, 2H, OCH₂),1.38 (t, J=7, 3H, OCH₂ CH₃). Analysis calculated for C₁₂ H₁₁ ClN₂ O₂ : C57.50; H 4.42; N 11.17. Found: C 57.49; H 4.46; N 11.16.

(b) A solution of the above product (0.44 g, 1.75 mmol) in EtOH (25 mL)and H₂ O (4 mL) was treated with KOH (85%, 0.81 g, 13 mmol) at refluxfor 4 h. Then, the reaction mixture was concentrated, partitionedbetween H₂ O and CHCl₃ and the organic phase was discarded. The aqueousphase was acidified to pH 1 with 6N HCl and the precipitate formed wasfiltered, washed with water and dried to give the title compound as awhite solid (0.32 g, 82%): mp 234°-235° C.; ¹ H NMR (80 MHz, CDCl₃) δ(TMS) 8.44 (s, 1H, pyrazole), 8.16 (s, 1H, pyrazole), 7.68 (dt,J_(t)=2,J_(d) =9, 2H, arom), 7.45 (dt,J_(t) =2,J_(d) =9, 2H, arom). Analysiscalculated for C₁₀ H₇ ClN₂ O₂ : C 53.95; H 3.17; N 12.58. Found: C53.31; H 3.30; N 12.60.

REFERENCE EXAMPLE 2 1-(4-Chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylicacid

The preparation of the following 5-substituted1-aryl-1H-pyrazole-4-carboxylic acids was carried out according to thegeneral procedure described in Menozzi, G. et al. J.Heterocyclic Chem.1987, 24, 1669. The following example illustrates this procedure:

(a) To a solution of ethyl acetylacetate (6 g, 46 mmol) in benzene (100mL) was slowly added a solution of dimethylformamide dimethylacetal (8.2g, 69 mmol) in benzene (100 mL) at 25° C. After the addition wascomplete, the reddish mixture was heated at reflux for 1 h and thenevaporated to dryness to give ethyl2-dimethylaminomethylene-3-oxobutanoate (8.66 g) as a reddish oil. Thisproduct (3.25 g, 17 mmol) was allowed to react with4-chlorophenylhydrazine hydrochloride (3.14 g, 17 mmol) in EtOH (50 mL)at reflux for 8 h. The mixture was evaporated to dryness and the productwas isolated by flash chromatography to give ethyl1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate as a white solid(2.07 g, 46%): mp 55°-56° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.02 (s,1H, pyrazole), 7.50 (d, J=9, 2H, arom), 7.34 (d, J=9, 2H, arom), 4.33(q, J=7, 2H, OCH₂), 2.56 (s, 3H, Me-pyrazole), 1.37 (t, J=7, 3H, OCH₂CH₃). Analysis calculated for C₁₃ H₁₃ ClN₂ O₂ : C 58.99; H 4.95; N10.58. Found: C 59.03; H 5.06; N 10.58.

(b) A solution of the product obtained in section (a) (1.91 g, 7.21mmol) in EtOH (50 mL) and H₂ O (10 mL) was treated with KOH (85%, 3.35g, 50 mmol) at 60° C. for 20 h. Then, the reaction mixture wasconcentrated and partitioned between H₂ O and CHCl₃. The organic phasewas discarded and the aqueous phase was acidified to pH 1 with 3N HCl.The precipitate formed was filtered, washed with water and dried to givethe title compound as a white solid (1.42 g, 83%): mp 195°-198° C.; ¹ HNMR (80 MHz, CDCl₃) δ (TMS) 8.39 (s, 1H, pyrazole), 7.50 (d, J=9, 2H,arom), 7.34 (d, J=9, 2H, arom), 2.59 (s, 3H, Me-pyrazole). Analysiscalculated for C₁₁ H₉ ClN₂ O₂ : C 55.83; H 3.83; N 11.84. Found: C56.10; H 3.82; N 11.54.

REFERENCE EXAMPLE 31-(4-Chlorophenyl)-5-isopropyl-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl1-(4-chlorophenyl)-5-isopropyl-1H-pyrazole-4-carboxylate was obtained asa white solid: mp 86°-87° C.; 1H NMR (80 MHz, CDCl₃) δ (TMS) 8.01 (s,1H, pyrazole), 7.48 (dt,J_(t) =2,J_(d) =9, 2H, arom), 7.28 (dt,J_(t)=2,J_(d) =9, 2H, arom), 4.33 (q, J=7, 2H, OCH₂), 3.28 (quint, J=7, 1H,Me₂ CH), 1.38 (t, J=7, 3H, OCH₂ CH₃), 1.35 (d, J=7, 6H, Me₂ CH).Analysis calculated for C₁₅ H₁₇ ClN₂ O₂ : C 61.54; H 5.85; N 9.57.Found: C 61.23; H 5.94; N 9.42.

(b) Following a similar procedure to that described in section b ofreference example 2 the title compound was obtained as a white solid: mp211°-212° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.11 (s, 1H, pyrazole),7.48 (dt,J_(t) =2,J_(d) =9, 2H, arom), 7.30 (dt,J_(t) =2,J_(d) =9, 2H,arom), 3.29 (quint, J=7,1H, Me₂ CH), 1.37 (t,J=7, 6H, Me₂ CH). Analysiscalculated for C₁₃ H₁₃ ClN₂ O₂ : C 58.99; H 4.95; N 10.58. Found: C59.23; H 4.93; N 10.47.

REFERENCE EXAMPLE 45-tertButyl-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl5-tertbutyl-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate was obtained asa white solid: mp 104°-105° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.96 (s,1H, pyrazole), 7.43 (dt,J_(t) =2,J_(d) =9, 2H, arom), 7.24 (dt,J_(t)=2,J_(d) =9, 2H, arom), 4.31 (q, J=7, 2H, OCH₂), 1.37 (t, J=7, 3H, OCH₂CH₃), 1.31 (s, 9H, Me₃ C). Analysis calculated for C₁₆ H₁₉ ClN₂ O₂ : C62.64; H 6.24; N 9.13. Found: C 62.67; H 6.28; N 9.12.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: ¹ H NMR (80 MHz,CDCl₃) δ (TMS) 8.09 (s, 1H, pyrazole), 7.45 (dt,J_(t) =2,J_(d) =9, 2H,arom), 7.26 (dt,J_(t) =2,J_(d) =9, 2H, arom), 1.34 (s, 9H, Me₃ C).Analysis calculated for C₁₄ H₁₅ ClN₂ O₂ : C 60.33; H 5.42; N 10.05.Found: C 60.41; H 5.41; N 10.12.

REFERENCE EXAMPLE 51-(4-Chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl1-(4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate was obtainedas a white solid: mp 64°-65° C.; 1H NMR (80 MHz, CDCl₃) δ (TMS) 8.00 (s,1H, pyrazole), 7.46 (s, 4H, arom), 4.33 (q, J=7, 2H, OCH₂), 2.2-1.8 (m,1H, c-prop), 1.37 (t, J=7, 3H, OCH₂ CH₃), 1.3-0.8 (m, 2H, c-prop),0.8-0.5 (m, 2H, c-prop). Analysis calculated for C₁₅ H₁₅ ClN₂ O₂ : C61.97; H 5.20; N 9.63. Found: C 61.64; H 5.26; N 9.65.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 186°-187° C.; ¹ HNMR (80 MHz, CDCl₃) δ (TMS) 8.09 (s, 1H, pyrazole), 7.46 (s, 4H, arom),2.2-1.8 (m, 1H, c-prop), 1.3-0.8 (m, 2H, c-prop), 0.8-0.5 (m, 2H,c-prop). Analysis calculated for C₁₃ H₁₁ ClN₂ O₂ : C 59.44; H 4.22; N10.66. Found: C 59.37; H 4.17; N 10.46.

REFERENCE EXAMPLE 65-Methyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate wasobtained as a white solid: mp 60°-61° C.; ¹ H NMR (80 MHz, CDCl₃) δ(TMS) 8.05 (s, 1H, pyrazole), 7.79 (d, J=9, 2H, arom), 7.58 (d, J=9, 2H,arom), 4.33 (q, J=7, 2H, OCH₂), 2.62 (s, 3H, Me-pyrazole), 1.38 (t, J=7,3H, OCH₂ CH₃). Analysis calculated for C₁₄ H₁₃ F₃ N₂ O₂ : C 56.38; H4.39; N 9.39. Found: C 56.34; H 4.36; N 9.32.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 186°-187° C.; ¹ HNMR (80 MHz, CDCl₃) δ (TMS) 8.14 (s, 1H, pyrazole), 7.80 (d, J=9, 2H,arom), 7.60 (d, J=9, 2H, arom), 2.64 (s, 3H, Me-pyrazole). Analysiscalculated for C₁₂ H₉ F₃ N₂ O₂ : C 53.34; H 3.36; N 10.37. Found: C53.68; H 3.38; N 10.22.

REFERENCE EXAMPLE 7 1-(4-Bromophenyl)-5-methyl-1H-pyrazole-4-carboxylicacid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylate was obtained as athick oil: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.02 (s, 1H, pyrazole), 7.63(dt,J_(t) =2,J_(d) =9, 2H, arom), 7.31 (dt,J_(t) =2, J_(d) =9, 2H,arom), 4.33 (q, J=7, 2H, OCH₂), 2.56 (s, 3H, Me-pyrazole), 1.37 (t, J=7,3H, OCH₂ CH₃). Analysis calculated for C₁₃ H₁₃ BrN₂ O₂ : C 50.51; H4.24; N 9.06. Found: C 50.34; H 4.57; N 8.93.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 213°-214° C.; 1HNMR (80 MHz, CDCl₃) δ (TMS) 8.10 (s, 1H, pyrazole), 7.65 (dt, J_(t)=1.5, J_(d) =9, 2H, arom), 7.31 (dt, J_(t) =1.5, J_(d) =9, 2H, arom),2.59 (s, 3H, Me-pyrazole). Analysis calculated for C₁₁ H₉ BrN₂ O₂ : C47.00; H 3.23; N 9.97. Found: C 47.01; H 3.21; N 9.99.

REFERENCE EXAMPLE 85-Trifluoromethyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylicacid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl5-trifluoromethyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylatewas obtained as a white solid: mp 45°-46° C.; ¹ H NMR (80 MHz, CDCl₃) δ(TMS) 8.14 (s, 1H, pyrazole), 7.90 (d, J=9, 2H, arom), 7.56 (d, J=9, 2H,arom), 4.38 (q, J=7, 2H, OCH₂), 1.39 (t, J=7, 3H, OCH₂ CH₃). Analysiscalculated for C₁₄ H₁₀ F₆ N₂ O₂ : C 47.74; H 2.86; N 7.95. Found: C47.89; H 2.92; N 7.95.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 157°-158° C.; ¹ HNMR (80 MHz, CDCl₃) δ (TMS) 8.23 (s, 1H, pyrazole), 7.82 (d, J=9, 2H,arom), 7.58 (d, J=9, 2H, arom). Analysis calculated for C₁₂ H₆ F₆ N₂ O₂: C 44.46 H 1.87; N 8.64. Found: C 44.76; H 1.82; N 8.50.

REFERENCE EXAMPLE 91-(3,5-Dichlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl1-(3,5-dichlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate was obtainedas a pale yellow solid: mp 85°-86° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS)8.02 (s, 1H, pyrazole), 7.5-7.3 (m, 3H, arom), 4.34 (q, J=7, 2H, OCH₂),2.61 (s, 3H, Me-pyrazole), 1.37 (t, J=7, 3H, OCH₂ CH₃). Analysiscalculated for C₁₃ H₁₂ Cl₂ N₂ O₂ : C 52.19; H 4.04; N 9.36. Found: C52.20; H 3.99; N 9.97.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 229°-230° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 7.98 (s, 1H, pyrazole), 7.40 (t, J=1.8, 1H,arom), 7.33 (t, J=1.8, 2H, arom), 2.54 (s, 3H, Me-pyrazole). Analysiscalculated for C₁₁ H₈ Cl₂ N₂ O₂ : C 48.73; H 2.97; N 10.33. Found: C48.92; H 2.89; N 10.40.

REFERENCE EXAMPLE 101-(2,6-Dichlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl1-(2,6-dichlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate was obtainedas colourless oil: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.12 (s, 1H,pyrazole), 7.6-7.4 (m, 3H, arom), 4.34 (q, J=7, 2H, OCH₂), 2.36 (s, 3H,Me-pyrazole), 1.38 (t, J=7, 3H, OCH₂ CH₃). Analysis calculated for C₁₃H₁₂ Cl₂ N₂ O₂ : C 52.19; H 4.04; N 9.36. Found: C 52.56; H 3.81; N 9.14.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 180°-182° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 8.20 (s, 1H, pyrazole), 7.6-7.4 (m, 3H,arom), 2.40 (s, 3H, Me-pyrazole). Analysis calculated for C₁₁ H₈ Cl₂ N₂O₂ : C 48.73; H 2.97; N 10.33. Found: C 48.82; H 2.90; N 10.20.

REFERENCE EXAMPLE 111-(2-Chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl1-(2-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate was obtained as acolourless oil: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.05 (s, 1H, pyrazole),7.6-7.4 (m, 4H, arom), 4.32 (q, J=7, 2H, OCH₂), 2.39 (s, 3H,Me-pyrazole), 1.37 (t, J=7, 3H, OCH₂ CH₃). Analysis calculated for C₁₃H₁₃ ClN₂ O₂ : C 58.99; H 4.95; N 10.58. Found: C 59.20; H 4.91; N 10.38.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 150°-151° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 8.14 (s, 1H, pyrazole), 7.6-7.4 (m, 4H,arom), 2.42 (s, 3H, Me-pyrazole). Analysis calculated for C₁₁ H₉ ClN₂ O₂: C 55.83; H 3.83; N 11.84. Found: C 56.03; H 3.91; N 11.93.

REFERENCE EXAMPLE 121-(4-Chlorophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 but reacting ethyl diacetylacetate with4-chlorophenylhydrazine hydrochloride, ethyl1-(4-chlorophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate was directlyobtained as a white solid: mp 79°-80° C.; ¹ H NMR (80 MHz, CDCl₃) δ(TMS) 7.47 (d, J=9, 2H, arom), 7.32 (d, J=9, 2H, arom), 4.32 (q, J=7,2H, OCH₂), 2.51 (s, 3H, Me-pyrazole), 2.49 (s, 3H, Me-pyrazole), 1.38(t, J=7, 3H, OCH₂ CH₃). Analysis calculated for C₁₄ H₁₅ ClN₂ O₂ : C60.33; H 5.42; N 10.05. Found: C 60.44; H 5.48; N 10.29.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 220°-223° C.; ¹ HNMR (80 MHz, CDCl₃) δ (TMS) 7.48 (d, J=9, 2H, arom), 7.34 (d, J=9, 2H,arom), 2.55 (s, 3H, Me-pyrazole), 2.52 (s, 3H, Me-pyrazole). Analysiscalculated for C₁₂ H₁₁ ClN₂ O₂ : C 57.50; H 4.42; N 11.17. Found: C57.60; H 4.43; N 11.19.

REFERENCE EXAMPLE 13 5-Amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylicacid

(a) A solution of ethyl ethoxymethylenecyanoacetate (3 g, 17.7 mmol) and4-chlorophenylhydrazine hydrochloride (3.33 g, 18.6 mmol) in ethanol (60mL) was refluxed for 2 days, following the procedure described inSchmidt, P. et al. Helv.Chim.Acta, 1959, 349. The reaction mixture wasthen allowed to cool to room temperature, whereupon a precipitate wasformed. Cold CHCl₃ was added, the precipitate was filtered and washedwith more CHCl₃. The filtrate and the washings were evaporated todryness, precipitated with ether, filtered and dried to give ethyl5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate (2.25 g, 48%) as awhite solid: mp 150°-156° C.; 1H NMR (80 MHz, CDCl₃) δ (TMS) 7.77 (s,1H, pyrazole), 7.48 (s, 4H, arom), 4.30 (q, J=7, 2H, OCH₂), 1.36 (t,J=7, 3H, OCH₂ CH₃). Analysis calculated for C₁₂ H₁₂ ClN₃ O₂ : C 54.25; H4.55; N 15.81. Found: C 54.77; H 4.49; N 15.65.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 169°-171° C.; ¹ HNMR (80 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.78 (s, 1H, pyrazole), 7.50 (s,4H, arom), 4.25 (br s, NH₂, OH). Analysis calculated for C₁₀ H₈ ClN₃ O₂: C 50.54; H 3.39; N 17.68. Found: C 50.54; H 3.39; N 17.44.

REFERENCE EXAMPLE 145-Amino-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid

(a) Following the procedure described in the reference example 13 ethyl5-amino-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate wasobtained as an amorphous white solid: ¹ H NMR (80 MHz, CDCl₃) δ (TMS)7.76 (s, 1H, pyrazole), 7.90 (d, J=9, 2H, arom), 7.56 (d, J=9, 2H,arom), 4.31 (q, J=7, 2H, OCH₂), 1.35 (t, J=7, 3H, OCH₂ CH₃). Analysiscalculated for C₁₃ H₁₂ F₃ N₃ O₂ : C 52.18; H 4.04; N 14.04. Found: C52.13; H 4.22; N 14.02

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 169°-171° C.; ¹ HNMR (80 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.78 (s, 1H, pyrazole), 7.90 (d,J=9, 2H, arom), 7.56 (d, J=9, 2H, arom), 4.32 (s, NH₂, OH). Analysiscalculated for C₁₁ H₈ F₃ N₃ O₂ : C 48.72; H 2.97; N 15.49. Found: C48.52; H 3.18; N 15.28.

REFERENCE EXAMPLE 155-Methyl-1-(3-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a orreference example 2 ethyl5-methyl-1-(3-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate wasobtained as a colourless oil: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.05 (s,1H, pyrazole), 7.8-7.5 (m, 4H, arom), 4.34 (q, J=7, 2H, OCH₂), 2.61 (s,3H, Me-pyrazole), 1.38 (t, J=7, 3H, OCH₂ CH₃). Analysis calculated forC₁₄ H₁₃ F₃ N₂ O₂ : C 56.38; H 4.39; N 9.39. Found: C 56.42; H 4.67; N9.13.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 122°-123° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 8.20 (s, 1H, pyrazole), 7.8-7.7 (m, 4H,arom), 2.69 (s, 3H, Me-pyrazole). Analysis calculated for Cl₂ H₉ F₃ N₂O₂ : C 53.34; H 3.36; N 10.37. Found: C 53.36; H 3.50; N 10.44.

REFERENCE EXAMPLE 165-Methyl-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl5-methyl-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carboxylate wasobtained as a colourless oil: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.02 (s,1H, pyrazole), 7.52 (d, J=9, 2H, arom), 7.32 (d, J=9, 2H, arom), 4.33(q, J=7, 2H, OCH₂), 2.57 (s, 3H, Me-pyrazole), 1.38 (t, J=7, 3H, OCH₂CH₃). Analysis calculated for C₁₄ H₁₃ F₃ N₂ O₃ : C 53.51; H 4.17; N8.91. Found: C 53.43; H 4.28; N 8.55.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 176°-178° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 8.46 (s, 1H, pyrazole), 7.55 (dt, J_(t)=2.8, J_(d) =8.8, 2H, arom), 7.43 (d, J=8.8, 2H, arom), 2.67 (s, 3H,Me-pyrazole). Analysis calculated for C₁₂ H₉ F₃ N₂ O₃ : C 50.36; H 3.17;N 9.79. Found: C 50.52; H 3.13; N 9.76.

REFERENCE EXAMPLE 171-(4-Methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

(a) Following a similar procedure to that described in section a ofreference example 2 ethyl1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylate was obtained as acolourless oil: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.99 (s, 1H, pyrazole),7.31 (d, J=9, 2H, arom), 6.99 (d, J=9, 2H, arom), 4.31 (q, J=7, 2H,OCH₂), 3.85 (s, 3H, OMe), 2.51 (s, 3H, Me-pyrazole), 1.34 (t, J=7, 3H,OCH₂ CH₃). Analysis calculated for C₁₄ H₁₆ N₂ O₃ : C 64.60; H 6.20; N10.76. Found: C 64.89; H 6.41; N 10.51.

(b) Following the procedure described in section b of reference example2 the title compound was obtained as a white solid: mp 212°-213° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 8.08 (s, 1H, pyrazole), 7.33 (d, J=8.8, 2H,arom), 7.01 (d, J=8.8, 2H, arom), 3.87 (s, 3H, OMe), 2.54 (s, 3H,Me-pyrazole). Analysis calculated for C₁₂ H₁₂ N₂ O₃ : C 62.06; H 5.21; N12.06. Found: C 62.23; H 2.13; N 12.06.

REFERENCE EXAMPLE 18 2-(4-Chlorophenyl)thiazole-5-carboxylic acid

(a) A solution of ethyl formylchloroacetate (1.45 g, 9.6 mmol; obtainedaccording to Panizzi, L. Gazz. Chim.Ital., 1946, 76, 56) and4-chlorothiobenzamide (1.76 g, 9.6 mmol) in EtOH (50 mL) was refluxedfor 48 h. The reaction mixture was then cooled to -20° C. and the solidformed was filtered and dried to give ethyl2-(4-chlorophenyl)thiazole-5-carboxylate (0.59 g, 23%): mp 144°-145° C.;¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.40 (s, 1H, thiazole), 7.92 (dt, J_(t)=1.8, J_(d) =8.6, 2H, arom), 7.44 (dt, J_(t) =1.8, J_(d) =8.6, 2H,arom), 4.39 (q, J=7, 2H, OCH₂), 1.40 (t, J=7, 3H, OCH₂ CH₃). Analysiscalculated for C₁₂ H₁₀ ClNO₂ S: C 53.84; H 3.76; N 5.23; S 11.97. Found:C 54.22; H 3.52; N 5.25; S 11.46.

(b) Following the hydrolysis procedure described in section b ofreference example 2 the title compound was obtained as a white solid: mp233°-234° C.; ¹ H NMR (300 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 8.31 (s, 1H,thiazole), 7.83 (dt, J_(t) =1.8, J_(d) =8.8, 2H, arom), 7.37 (dt, J_(t)=1.8, J_(d) =8.8, 2H, arom). Analysis calculated for C₁₀ H₆ ClNO₂ S: C50.11; H 2.52; N 5.84; S 13.38. Found: C 49.37; H 2.41; N 5.54; S 11.90.

REFERENCE EXAMPLE 19 4-Methyl-2-phenylthiazole-5-carboxylic acid

(a) A solution of methyl 2-chloroacetoacetate (1.86 g, 12.4 mmol) andthiobenzamide (1.7 g, 12.4 mmol) in EtOH (50 mL) was refluxed for 18 h.The mixture was evaporated to dryness and the resulting oil was purifiedby flash chromatography to give methyl4-methyl-2-phenylthiazole-5-carboxylate (1.21 g, 42%) as a colourlessoil: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.0-7.9 (m, 2H, arom), 7.5-7.4 (m,3H, arom), 3.87 (s, 3H, OMe), 2.76 (s, 3H, Me-thiazole). Analysiscalculated for C₁₂ H₁₁ NO₂ S: C 61.78; H 4.75; N 6.00; S 13.74. Found: C61.56; H 4.71; N 5.82; S 14.61.

(b) Following the hydrolysis procedure described in section b ofreference example 2 but using MeOH as solvent and heating at 80° C. for4 h the title compound was obtained as a white solid: mp 215°-218° C,; ¹H NMR (300 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.9-7.8 (m, 2H, arom), 7.4-7.3(m, 3H, arom), 2.66 (s, 3H, Me-thiazole). Analysis calculated for C₁₁ H₉NO₂ S: C 60.26 H 4.14; N 6.39; S 14.62. Found: C 60.37; H 4.07; N 6.14;S 14.91.

REFERENCE EXAMPLE 20 2-(4-Chlorophenyl)-4-methylthiazole-5-carboxylicacid

(a) Following the procedure described in section a of reference example19 methyl 2-(4-chlorophenyl)-4-methylthiazole-5-carboxylate was obtainedas a white solid: mp 132°-133° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.89(dt, J_(t) =1.8, J_(d) =8.8, 2H, arom), 7.40 (dt, J_(t) =1.8, J_(d)=8.8, 2H, arom), 3.89 (s, 3H, OMe), 2.77 (s, 3H, Me-thiazole). Analysiscalculated for C₁₂ H₁₀ ClNO₂ S: C 53.84; H 3.76; N 5.23; S 11.97. Found:C 54.09; H 3.78; N 5.10; S 12.27.

(b) Following the hydrolysis procedure described in section b ofreference example 19 the title compound was obtained as a white solid:mp 256°-263° C.; ¹ H NMR (300 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.84 (dt,J_(t) =1.8, J_(d) =8.8, 2H, arom), 7.40 (dt, J_(t) =1.8, J_(d) =8.8, 2H,arom), 2.70 (s, 3H, Me-thiazole). Analysis calculated for C₁₁ H₈ ClNO₂S: C 52.08; H 3.18; N 5.52; S 12.64. Found: C ) 49.88; H 2.93; N 5.15; S11.20.

REFERENCE EXAMPLE 21 2-(4-Bromophenyl)-4-methylthiazole-5-carboxylicacid

(a) Following the procedure described in section a of reference example19 methyl 2-(4-bromophenyl)-4-methylthiazole-5-carboxylate was obtainedas a white solid: mp 144°-146° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.84(dt, J_(t) =2, J_(d) =8.6, 2H, arom), 7.57 (dt, J_(t) =2, J_(d) =8.6,2H, arom), 3.89 (s, 3H, OMe), 2.77 (s, 3H, Me-thiazole). Analysiscalculated for C₁₂ H₁₀ BrNO₂ S: C 46.17; H 3.23; N 4.49; S 10.27. Found:C 45.95; H 3.27; N 4.52; S 10.34.

(b) Following the hydrolysis procedure described in section b ofreference example 19 the title compound was obtained as a white solid:mp 227° C. (dec); ¹ H NMR (80 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.85 (dt,J_(t) =1.8, J_(d) =8.8, 2H, arom), 7.40 (dt, J_(t) =1.8, J_(d) =8.8, 2H,arom), 2.79 (s, 3H, Me-thiazole). Analysis calculated for C₁₁ H₈ BrNO₂S: C 44.31; H 2.70; N 4.70; S 10.75. Found: C 44.02; H 3.09; N 4.45; S10.36.

REFERENCE EXAMPLE 224-Methyl-2-(4-trifluoromethoxyphenyl)thiazole-5-carboxylic acid

(a) Following the procedure described in section a of reference example19 methyl 4-methyl-2-(4-trifluoromethoxyphenyl)thiazole-5-carboxylatewas obtained as a white solid: mp 76°-77° C.; ¹ H NMR (80 MHz, CDCl₃) δ(TMS) 8.00 (dt, J_(t) =2, J_(d) =8.8, 2H, arom), 7.30 (dt, J_(t) =2,J_(d) =8.8, 2H, arom), 3.90 (s, 3H, OMe), 2.78 (s, 3H, Me-thiazole).Analysis calculated for C₁₃ H₁₀ F₃ NO₃ s: C 49.21; H 3.18; N 4.41; S10.10. Found: C 49.23; H 3.40; N 4.36; S 10.37.

(b) Following the hydrolysis procedure described in section b ofreference example 19 the title compound was obtained as a white solid:mp 179°-181° C.; ¹ H NMR (80 MHz, CDCl₃) 8 (TMS) 8.00 (dt, J_(t) =1.8,J_(d) =8.8, 2H, arom), 7.30 (dt, J_(t) =1.8, J_(d) =8.8, 2H, arom), 2.81(s, 3H, Me-thiazole). Analysis calculated for C₁₂ H₈ F₃ NO₃ S: C 47.53;H 2.66; N 4.62; S 10.57. Found: C 47.59; H 2.68; N 4.62; S 10.26.

REFERENCE EXAMPLE 23 4-Methyl-2-4-(2,2,3,3-tetrafluoropropoxy)phenyl!thiazole-5carboxylic acid

(a) Following the procedure described in section a of reference example19 methyl 4-methyl-2-4-(2,2,3,3-tetrafluoropropoxy)phenyl!thiazole-5-carboxylate was obtainedas a white solid: mp 102°-103° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.95(dt, J_(t) =2, J_(d) =8.8, 2H, arom), 7.00 (dt, J_(t) =2, J_(d) =8.8,2H, arom), 6.06 (tt, J=4.6, J=53, 1H, CHF₂), 4.41 (tt, J=1.5, J=11.8,2H, CH₂), 3.89 (s, 3H, OMe), 2.77 (s, 3H, Me-thiazole). Analysiscalculated for C₁₅ H₁₃ F₄ NO₃ S: C 49.59; H 3.61; N 3.86; S 8.82. Found:C 49.76; H 3.73; N 3.89; S 8.66.

(b) Following the hydrolysis procedure described in section b ofreference example 19 the title compound was obtained as a white solid:mp 167°-168° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.95 (dt, J_(t) =1.8,J_(d) =8.8, 2H, arom), 7.00 (dt, J_(t) =1.8, J_(d) =8.8, 2H, arom), 6.05(tt, J=4.6, J=53, 1H, CHF₂), 4.41 (tt, J=1.5, J=11.8, 2H, CH₂), 2.79 (s,3H, Me-thiazole). Analysis calculated for C₁₄ H₁₁ F₄ NO₃ S: C 48.14; H3.17; N 4.01; S 9.18. Found: C 48.20; H 3.19; N 3.71; S 8.72.

REFERENCE EXAMPLE 24 2-(4-Cyanophenyl)-4-methylthiazole-5-carboxylicacid

(a) A suspension of methyl 2-chloroacetoacetate (30 g, 0.19 mol) and4-cyanothiobenzamide (21.5 g, 0.13 mol) in MeOH (250 mL) was refluxedfor 15 h. The reaction mixture was then cooled to 0° C., filtered after20 h and washed with cooled (-20° C.) MeOH and with ether. The resultingoff-white solid was dried to give methyl2-(4-cyanophenyl)-4-methylthiazole-5-carboxylate (18.7 g, 55%). Ifdesired, additional product may be recovered by flash chromatography ofthe washings: mp 186°-187° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.07(dt, J_(t) =1.6, J_(d) =8.3, 2H, arom), 7.74 (dt, J_(t) =1.6, J_(d)=8.3, 2H, arom), 3.91 (s, 3H, OMe), 2.79 (s, 3H, Me-thiazole). Analysiscalculated for C₁₃ H₁₀ N₂ O₂ S: C 60.45; H 3.90; N 10.85; S 12.41.Found: C 60.31; H 3.80; N 10.53; S 11.79.

(b) The product obtained in section (a) (18.7 g, 72.4 mmol) wasdissolved in a mixture of MeOH (0.6L) and THF (0.3L). Next, a solutionof LiOH.H₂ O (15.2 g, 0.36 mol) in 60 mL of water was slowly added andthe resulting reddish mixture was stirred at 30° C. for 8 h. The mixturewas then evaporated to dryness, water was added to the residue, then itwas filtered through celite and was acidified with 3N HCl to pH 1.0-1.2,resulting in the appearance of an orange foamy material. This product,which was difficult to filter, was centrifuged, washed with cold water,centrifuged again and then dried to give the title compound as ayellowish solid (18 g, 100%): mp 235-250° C.; ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 8.15 (dt, J_(t) =1.6, J_(d) =8.3, 2H, arom), 7.84 (dt, J_(t) =1.6,J_(d) =8.3, 2H, arom), 2.74 (s, 3H, Me-thiazole). Analysis calculatedfor C₁₂ H₈ N₂ O₂ S: C 59.01; H 3.30; N 11.47; S 13.12. Found: C 59.31; H3.18; N 11.68; S 13.01.

REFERENCE EXAMPLE 25 2-2-(4-Chlorophenyl)-4-methylthiazol-5-yl!-4-methylthiazole-5-carboxylicacid

(a) A solution of 2-(4-chlorophenyl)-4-methylthiazole-5-carboxylic acid(0.78 g, 3 mmol; obtained in reference example 20) in thionyl chloride(10 mL) was refluxed for 4 h. The reaction mixture was evaporated todryness, the resulting residue (0.93 g) was taken up in THF (15 mL) andthen was slowly added to a cooled (0° C.) 40% ammonium hydroxidesolution. Volatiles were removed in vacuo and the resulting aqueousresidue was filtered and dried to give2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (0.63 g, 79%) as awhite solid: mp 236°-237° C.; ¹ H NMR (300 MHz, CDCl₃ +MeOH--d₄) δ (TMS)7.80 (d, J=8.4, 2H, arom), 7.36 (d, J=8.4, 2H, arom), 2.66 (s, 3H,Me-thiazole).

(b) To a solution of the product obtained in section (a) (0.89 g, 3.52mmol) in a mixture of toluene (15 mL) and THF (15 mL) was addedLawesson's reagent (0.85 g, 2.11 mmol) and the resulting yellow solutionwas refluxed for 2 h. The reaction mixture was evaporated to dryness andthe resulting product(2-(4-chlorophenyl)-4-methylthiazole-5-carbothioamide, 2.19 g) was thenallowed to react with methyl 2-chloroacetoacetate in a similar manner tothat described in section a of reference example 19. Methyl 2-2-(4-chlorophenyl)-4-methylthiazol-5-yl!-4-methylthiazole-5-carboxylatewas isolated by flash chromatography as a yellow solid (0.59 g, 46%): mp174°-175° C.; ¹ H NMR (300 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.90 (d, J=8.4,2H, arom), 7.42 5 (d, J=8.4, 2H, arom), 3.91 (s, 3H, OMe)), 2.766 (s,3H, Me-thiazole), 2.761 (s, 3H, Me-thiazole). Analysis calculated forC₁₆ H₁₃ ClN₂ O₂ S₂ : C 52.67; H 3.59; N 7.68; S 17.57. Found: C 52.53; H3.87; N 7.29; S 17.01.

(c) Following the hydrolysis procedure described in section b ofreference example 2 the title compound was obtained as a slightlyyellowish solid: mp 265°-268° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.15(dt, J_(t) =1.6, J_(d) =8.3, 2H, arom), 7.84 (dt, J_(t) =1.6, J_(d)=8.3, 2H, arom), 2.74 (s, 6H, Me-thiazole). Analysis calculated for C₁₅H₁₁ ClN₂ O₂ S₂ : C 51.35; H 3.16; N 7.98; S 18.28. Found: C 51.32; H3.12; N 7.78; S 17.43.

REFERENCE EXAMPLE 262-(4-Chlorophenyl)-4-trifluoromethylthiazole-5-carboxylic acid

(a) Following the procedure described in section a of reference example19 but using ethyl 2-chloro-4,4,4-trifluoroacetoacetate and4-chlorophenylthiobenzamide, ethyl2-(4-chlorophenyl)-4-trifluoromethyl-thiazole-5-carboxylate was obtainedas a white solid, unpurified with a small amount of starting material: ¹H NMR (300 MHz, CDCl₃) δ (TMS) 7.81 (dt, J_(t) =2.4, J_(d) =8.7, 2H,arom), 7.42 (dt, J_(t) =2.4, J_(d) =8.7, 2H, arom), 4.3-4.2 (m, 2H,OCH₂), 1.32 (t, J=7, 3H, OCH₂ CH₃).

(b) Following the hydrolysis procedure described in section b ofreference example 19 the title compound was obtained as a white solid:mp 235°-250° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.95 (dt, J_(t) =2.4,J_(d) =8.7, 2H, arom), 7.43 (d, J=8.3, 2H, arom). Analysis calculatedfor C₁₁ H₅ ClF₃ NO₂ S: C 42.94; H 1.64; N 4.55; S 10.42. Found: C 43.34;H 1.66; N 4.48; S 9.93.

REFERENCE EXAMPLE 274-Trifluoromethyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxylic acid

(a) Following the procedure described in section a of reference example19 but using ethyl 2-chloro-4,4,4-trifluoroacetoacetate and4-trifluoromethylphenylthiobenzamide, ethyl4-trifluoromethyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxylate wasobtained as a white solid, which still contained a small amount ofstarting material: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.01 (d, J=8.1, 2H,arom), 7.71 (d, J=8.1, 2H, arom), 4.3-4.2 (m, 2H, OCH₂), 1.34 (t, J=7,3H, OCH₂ CH₃).

(b) Following the hydrolysis procedure described in section b ofreference example 19 the title compound was obtained as a white solid:mp 177°-179° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.14 (d, J=8.2, 2H,arom), 7.75 (d, J=8.2, 2H, arom). Analysis calculated for C₁₂ H₅ F₆ NO₂S: C 42.24; H 1.48; N 4.10; S 9.40. Found: C 41.86; H 1.33; N 4.03; S8.92.

REFERENCE EXAMPLE 282-(4-Cyanophenyl)-4-trifluoromethylthiazole-5-carboxylic acid

(a) Following the procedure described in section a of reference example24 but using ethyl 2-chloro-4,4,4-trifluoroacetoacetate, ethyl2-(4-cyanophenyl)-4-trifluoromethylthiazole-5-carboxylate was obtainedas a white solid, which still contained a small amount of startingmaterial.

(b) Following the hydrolysis procedure described in section b ofreference example 24 the title compound was obtained as a white solid:mp 195°-196° C.; ¹ H NMR (300 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 8.10 (d,J=8.1, 2H, arom), 7.78 (d, J=8.1, 2H, arom). Analysis calculated for C₁₂H₅ F₃ N₂ O₂ S: C 48.33; H 1.69; N 9.39; S 10.75. Found: C 48.36; H 1.88;N 9.08; S 9.97.

REFERENCE EXAMPLE 29 2-(4-Chlorophenoxy)methyl!-4-methylthiazole-5-carboxylic acid

(a) Following the procedure described in section a of reference example19 methyl 2- (4-chlorophenoxy)methyl!-4-methylthiazole-5-carboxylate wasobtained as a white solid: mp 88°-89° C.; ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 7.25 (dt, J_(t) =2.1, J_(d) =8.9, 2H, arom), 6.90 (dt, J_(t) =2.1,J_(d) =8.9, 2H, arom), 5.27 (s, 2H, CH₂ O), 3.86 (s, 3H, OMe), 2.73 (s,3H, Me-thiazole). Analysis calculated for C₁₃ H₁₂ ClNO₃ S: C 52.44; H4.06; N 4.70; S 10.77. Found: C 51.09; H 4.03; N 5.18; S 10.19.

(b) Following the hydrolysis procedure described in section b ofreference example 24, but allowing the reaction to proceed overnight,the title compound was obtained as a white solid: mp 233°-234° C.; ¹ HNMR (300 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.21 (dt, J_(t) =2.2, J_(d) =9,2H, arom), 6.88 (dt, J_(t) =2.2, J_(d) =9, 0 2H, arom), 5.22 (s, 2H, CH₂O), 2.66 (s, 3H, Me-thiazole). Analysis calculated for C₁₂ H₁₀ ClNO₃ S:C 50.80; H 3.55; N 4.94; S 11.30. Found: C 51.13; H 3.57; N 4.97; S11.12.

REFERENCE EXAMPLE 30 2-N-(4-Chlorophenyl)amino!-4-methylthiazole-5-carboxylic acid

(a) Following the procedure described in section a of reference example19, but using 4-chlorophenylthiourea, methyl 2-N-(4-chlorophenyl)amino!-4-methylthiazole-5-carboxylate was obtained asa white solid: mp 172°-173° C.; ¹ H NMR (300 MHz, CDCl₃ +MeOH--d₄) δ(TMS) 7.43 (dt, J_(t) =2.3, J_(d) =8.9, 2H, arom), 7.34 (dt, J_(t) =2.3,J_(d) =8.9, 2H, arom), 4.07 (br s, 1H, NH), 3.83 (s, 3H, OMe), 2.64 (s,3H, Me-thiazole). Analysis calculated for C₁₂ H₁₁ ClN₂ O₂ S: C 50.98; H3.92; N 9.91; S 11.34. Found: C 51.21; H 3.80; N 9.81; S 10.11.

(b) Following the hydrolysis procedure described in section b ofreference example 2 but heating the reaction at reflux overnight thetitle compound was obtained as a white solid: mp>250° C.; ¹ H NMR (300MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.40 (dt, J_(t) =2.1, J_(d) =9, 2H, arom),7.30 (dt, J_(t) =2.1, J_(d) =9, 2H, arom), 2.58 (s, 3H, Me-thiazole).Analysis calculated for C₁₁ H₉ ClN₂ O₂ S: C 49.17; H 3.38; N 10.42; S11.93. Found: C 49.29; H 3.31; N 10.32; S 11.32.

REFERENCE EXAMPLE 31 2-(4-Chlorophenyl)thiazole-4-carboxylic acid

(a) A solution of ethyl bromopyruvate (354 mg, 1.8 mmol) and4-chlorothiobenzamide (283 g, 1.65 mmol) in EtOH (40 mL) was refluxedfor 3 h. The mixture was evaporated to dryness and the resulting oil waspurified by flash chromatography to give ethyl2-(4-chlorophenyl)thiazole-4-carboxylate as a colourless oil: ¹ H NMR(80 MHz, CDCl₃) δ (TMS) 8.15 (s, 1H, thiazole), 7.95 (dt, J_(t) =2,J_(d) =8.5, 2H, arom), 7.42 (dt, J_(t) =2, J_(d) =8.5, 2H, arom), 4.45(q, J=7, 2H, OCH₂), 1.43 (t, J=7, 3H, OCH₂ CH₃). Analysis calculated forC₁₂ H₁₀ ClNO₂ S: C 53.84; H 3.76; N 5.23; S 11.97. Found: C 53.65; H3.77; N 5.23; S 11.51.

(b) Following the hydrolysis procedure described in section b ofreference example 2 but heating the solution overnight, the titlecompound was obtained as a white solid: mp 189°-190° C.; ¹ H NMR (80MHz, CDCl₃) δ (TMS) 8.29 (s, 1H, thiazole), 7.93 (dt, J_(t) =2, J_(d)=8.5, 2H, arom), 7.45 (dt, J_(t) =2, J_(d) =8.5, 2H, arom). Analysiscalculated for C₁₀ H₆ ClNO₂ S: C 50.11 H 2.52; N 5.84; S 13.35. Found: C50.21; H 2.45; N 5.79; S 13.21.

REFERENCE EXAMPLE 32 2-(4-Trifluoromethylphenyl)thiazole-4-carboxylicacid

(a) Following the procedure described in section a of reference example31 ethyl 2-(4-trifluoromethylphenyl)thiazole-4-carboxylate was obtainedas a white solid: mp 102°-103° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.21(s, 1H, thiazole), 8.15 (d, J=8.3, 2H, arom), 7.71 (d, J=8.3, 2H, arom),4.47 (q, J=7, 2H, OCH₂), 1.44 (t, J=7, 3H, OCH₂ CH₃). Analysiscalculated for C₁₃ H₁₀ F₃ NO₂ S: C 51.83; H 3.35; N 4.65; S 10.64.Found: C 51.91; H 3.34; N 4.61; S 10.29.

(b) Following the hydrolysis procedure described in section b ofreference example 31 the title compound was obtained as a white solid:mp 188°-189° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.37 (s, 1H, thiazole),8.13 (d, J=8.5, 2H, arom), 7.73 (d, J=8.5, 2H, arom). Analysiscalculated for C₁₁ H₆ F₃ NO₂ S: C 48.36 H 2.21; N 5.13; S 11.73. Found:C 48.46; H 2.22; N 5.17; S 11.75.

REFERENCE EXAMPLE 33 2-Phenylthiazole-4-carboxylic acid

(a) Following the procedure described in section a of reference example31 ethyl 2-phenylthiazole-4-carboxylate was obtained as a colourlessoil: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.14 (s, 1H, thiazole), 8.1-7.8 (m,2H, arom), 7.6-7.2 (m, 3H, arom), 4.45 (q, J=7, 2H, OCH₂), 1.42 (t, J=7,3H, OCH₂ CH₃).

(b) Following the hydrolysis procedure described in section b ofreference example 31 the title compound was obtained as an amorphouswhite solid: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.27 (s, ¹ H, thiazole),8.2-7.8 (m, 2H, arom), 7.6-7.4 (m, 3H, arom).

REFERENCE EXAMPLE 34 2-4-(2,2,3,3-Tetrafluoropropoxy)phenyl!thiazole-4-carboxylic acid

(a) Following the procedure described in section a of reference example31 ethyl 2- 4-(2,2,3,3-tetrafluoropropoxy)phenyl!thiazole-4-carboxylatewas obtained as a colourless oil: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.11(s, ¹ H, thiazole), 7.98 (dt, J_(t) =2, J_(d) =8.8, 2H, arom), 6.98 (dt,J_(t) =2, J_(d) =8.8, 2H, arom), 6.06 (tt, J=4.6,J=53, 1H, CHF₂), 4.41(tt, J=1.5, J=11.8, 2H, CH₂), 4.35 (q,J=7, 2H, OCH₂), 1.42 (t, J=7, 3H,OCH₂ CH₃).

(b) Following the hydrolysis procedure described in section b ofreference example 31 the title compound was obtained as a white solid:mp 170°-173° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.95 (s, 1H, thiazole),8.70 (dt, J_(t) =2, J_(d) =8.8, 2H, arom), 7.75 (dt, J_(t) =2, J_(d)=8.8, 2H, arom), 6.79 (tt, J=4.6, J=53, 1H, CHF₂), 5.16 (tt, J=1.5,J=11.8, 2H, CH₂).

REFERENCE EXAMPLE 35 5-(4-Cyanophenyl)thiophene-2-carboxylic acid

(a) Following the procedure described in Hauptmann et al, TetrahedronLett. 1968, 1317, ethyl 5-(4-cyanophenyl)thiophene-2-carboxylate wasobtained as a white solid: mp 133°-134° C.; ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 7.83 (d, J=4, 1H, thiophene), 7.81 (dt, J_(t) =1.6, J_(d) =8.3,2H, arom), 7.70 (dt, J_(t) =1.6, J_(d) =8.3, 2H, arom), 7.43 (d, J=4,1H, thiophene), 4.44 (q, J=7, 2H, OCH₂), 1.45 (t, J=7, 3H, OCH₂ CH₃).Analysis calculated for C₁₄ H₁₁ NO₂ S: C 65.35; H 4.31; N 5.44; S 12.46.Found: C 64.92; H 4.19; N 5.34; S 12.19.

(b) Following the hydrolysis procedure described in section b ofreference example 24 the title compound was obtained as a white solid:mp>300° C.; ¹ H NMR (300 MHz, DMSO--d₆) δ (TMS) 7.99 (d, J=8.3, 2H,arom), 7.87 (d, J=8.3, 2H, arom), 7.74 (s, 2H, thiophene).

REFERENCE EXAMPLE 36 5-(4-Chlorophenyl)-3-methylthiophene-2-carboxylicacid

(a) To a cooled (-78° C.) solution of3-(4-chlorophenyl)-3-chloroacrolein (2.0 g, 10.4 mmol, obtainedaccording to Hauptmann et al, Tetrahedron Lett. 1968, 1317) in dry THF(30 mL) was added dropwise a 3M solution of methylmagnesium bromide inTHF (3.47 mL, 10.4 mmol). After the addition was complete, the reactionmixture was stirred at -78° C. for 0.5 h. Next, saturated aqueous NH₄ Clsolution was added and the mixture was concentrated. The resultingaqueous residue was extracted with CHCl₃, dried, filtered, concentratedand purified by flash chromatography to give4-(4-chlorophenyl)-4-chloro-3-buten-2-ol (1.54 g, 71%) as a colourlessoil: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.51 (dt, J_(t) =2.6, J_(d) =8.6,2H, arom), 7.33 (dt, J_(t) =2.6, J_(d) =8.6, 2H, arom), 6.18 (d, J=7.5,1H, ═CH), 4.93 (quint, J=6.4, 1H, CHOH), 1.39 (d, J=6.4, 3H, CHCH₃).

(b) CH₂ Cl₂ (160 mL), pyridine (14 mL, 0.175mol) and CrO₃ (8.76 g, 87mmol) were placed in a flask. The resulting reddish solution was cooledto 0° C., stirred for 0.5 h, and a solution of4-(4-chlorophenyl)-4-chloro-3-buten-2-ol (2.8 g, 14.6 mmol, obtained inthe preceding section) in CH₂ Cl₂ (20 mL) was added dropwise. Thereaction mixture was then stirred at room temperature for 4 h, filteredthrough celite, washed, concentrated and purified by flashchromatography to afford 4-(4-chlorophenyl)-4-chloro-3-buten-2-one as acolourless oil (1.3 g, 45%): ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.61 (dt,J_(t) =2.6, J_(d) =8.6, 2H, arom), 7.39 (dt, J_(t) =2.6, J_(d) =8.6, 2H,arom), 6.75 (s, 1H, ═CH), 2.47 (5, 3H, Me).

(c) Following the procedure described in the literature (see referenceexample 35), the compound obtained in section (b) was allowed to reactwith the sodium salt of ethyl mercaptoacetate to give ethyl5-(4-chlorophenyl)-3-methylthiophene-2-carboxylate as an amorphoussolid: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.54 (dt, J_(t) =2.5, J_(d) =9,2H, arom), 7.37 (dt, J_(t) =2.5, J_(d) =9, 2H, arom), 7.11 (s, 1H,thiophene), 4.35 (q, J=7, 2H, OCH₂), 2.57 (s, 3H, Me-thiophene), 1.40(t, J=7, 3H, OCH₂ CH₃).

(d) Following the hydrolysis procedure described in section b ofreference example 2 the title compound was obtained as a white solid: mp245°-246° C.; ¹ H NMR (300 MHz, MeOH--d₄) δ (MeOH) 7.63 (dt, J_(t) =2,J_(d) =8.6, 2H, arom), 7.39 (dt, J_(t) =2, J_(d) =8.6, 2H, arom), 7.25(s, 1H, thiophene), 2.52 (s, 3H, Me-thiophene). Analysis calculated forC₁₂ H₉ ClO₂ S: C 57.03; H 3.59; S 12.69. Found: C 56.94; H 3.20; S12.39.

REFERENCE EXAMPLE 37 5-(4-Cyanophenyl)-3-methylthiophene-2-carboxylicacid

(a) Following the procedure described in reference example 36a4-(4-cyanophenyl)-4-chloro-3-buten-2-ol was obtained as a colourlessoil: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.70 (dt, J_(t) =2.1, J_(d) =8.7,2H, arom), 7.64 (dt, J_(t) =2.1, J_(d) =8.7, 2H, arom), 6.33 (d, J=7.5,1H, ═CH), 4.95 (quint, J=6.5, 1H, CHOH), 1.41 (d, J=6.5, 3H, CHCH₃).

(b) Following the procedure described in reference example 36b4-(4-cyanophenyl)-4-chloro-3-buten-2-one was obtained as a colourlessoil: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.79 (dt, J_(t) =2.2, J_(d) =8.7,2H, arom), 7.71 (dt, J_(t) =2.2, J_(d) =8.7, 2H, arom), 6.79 (s, 1H,═CH), 2.49 (s, 3H, Me).

(c) Following the procedure described in reference example 36c ethyl5-(4-cyanophenyl)-3-methylthiophene-2-carboxylate was obtained as awhite solid: mp 129°-130° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.68 (s,4H, arom), 7.19 (s, 1H, thiophene), 4.35 (q, J=7, 2H, OCH₂), 2.57 (s,3H, Me-thiophene), 1.39 (t, J=7, 3H, OCH₂ CH₃).

(d) Following the hydrolysis procedure described in section b ofreference example 24 the title compound was obtained as a white solid:mp 248°-253° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.68 (d, J=9, 2H,arom), 7.66 (d, J=9, 2H, arom), 7.20 (s, 1H, thiophene), 2.53 (s, 3H,Me-thiophene). Analysis calculated for C₁₃ H₉ NO₂ S: C 64.18; H 3.73; N5.76; S 13.18. Found: C 64.18; H 3.71; N 5.60; S 13.00.

REFERENCE EXAMPLE 382-(4-Chlorophenyl)-5-methyl-3H-imidazole-4-carboxylic acid

(a) A solution of ethyl 2-oximinoacetoacetate (6 g, 38 mmol; obtainedaccording to Org.Synth. 1941, 21, 67) in MeCN (75 mL) was treated with4-chlorobenzylamine (5.6 g, 40 mmol) at reflux for 18 h. Next, thereaction mixture was allowed to cool and the yellow solid formed wascollected by filtration to give ethyl2-(4-chlorophenyl)-5-methyl-3H-imidazole-4-carboxylate as a white solid(4.1 g, 40%): mp 237°-238° C.; ¹ H NMR (300 MHz, DMSO--d₆) δ (DMSO) 7.96(d, J=8, 2H, arom), 7.57 (d, J=8, 2H, arom), 4.27 (q, J=7, 2H, OCH₂),2.54 (s, 3H, Me-imidazole), 1.33 (t, J=7, 3H, OCH₂ CH₃). Analysiscalculated for C₁₃ H₁₃ ClN₂ O₂ : C 58.99; H 4.95; N 10.58. Found: C59.20; H 4.95; N 10.59.

(b) Following the hydrolysis procedure described in section b ofreference example 2 the title compound was obtained as a white solid: ¹H NMR (300 MHz, DMSO--d₆) δ (DMSO) 7.98 (br), 7.50 (d, J=8.5, 2H, arom),2.49 (s, 3H, Me-imidazole).

REFERENCE EXAMPLE 39 Mixture of2-(4-chlorophenyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid and2-(4-chlorophenyl)-1,5-dimethyl-1H-imidazole-4-carboxylic acid

A solution of ethyl2-(4-chlorophenyl)-5-methyl-3H-imidazole-4-carboxylate (2.7 g, 10 mmol,obtained in reference example 38) in DMF (50 mL) was treated with K₂ CO₃(1.4 g, 10 mmol) and Mel (0.95 mL, 15.3 mmol) at 60° C. for 2 h. Themixture was then evaporated to dryness and the resulting residuepartitioned between EtOAc and water. The organic phase was separated,dried over Na₂ SO₄, filtered and concentrated to afford a ca. 1:1mixture of N-methylimidazole derivatives. This mixture was thenhydrolyzed as described above to give a mixture of acids N-methylated onthe imidazole ring. This mixture was directly used in the next step asobtained.

REFERENCE EXAMPLE 40 5-(4-Chlorophenyl)-1,3,4-oxadiazole-2-carboxylicacid

(a) This product was prepared by a modification of the general proceduredescribed in Dost, J. et al. J.Prakt.Chem.1985, 327, 109. To a cooled(0° C.) solution of 4-chlorobenzhydrazide (5 g, 29 mmol) andtriethylamine (7.4 mL, 51 mmol) in CH₂ Cl₂ (100 mL) was added dropwiseethyl oxalyl chloride (4 g, 29 mmol) and the mixture was stirred for 3h. Next, saturated NaHCO₃ solution (50 mL) and CHCl₃ were added. Theorganic phase was dried over anhydrous Na₂ SO₄, filtered andconcentrated to give ethyl 4-chlorobenzoylhydrazinooxalate as acolourless oil which was purified by flash chromatography to yield 1.1 gof a white solid. This product was then dissolved in POCl₃ (30 mL) andheated at 100° C. for 15 h. The reaction mixture was evaporated todryness and partitioned between 10% aqueous NaHCO₃ and CHCl₃. Theorganic phase was separated, dried over anhydrous Na₂ SO₄, filtered andconcentrated. The residue was purified by flash chromatography to affordethyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate as a white solid(450 mg): mp 117°-118° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.11 (dt,J_(t) =2.3, J_(d) =8.6, 2H, arom), 7.54 (dt, J_(t) =2.3, J_(d) =8.6, 2H,arom), 4.56 (q, J=7.1, 2H, OCH₂), 1.49 (t, J=7.1, 3H, OCH₂ CH₃).Analysis calculated for C₁₁ H₉ ClN₂ O₃ : C 52.29; H 3.59; N 11.09.Found: C 52.70; H 3.42; N 10.89.

(b) Following the hydrolysis procedure described in section b ofreference example 2, the title compound was obtained as a white solid:mp 277°-284° C.; ¹ H NMR (300 MHz, MeOH--d₄) δ (MeOH) 7.87 (d, J=8.5,2H, arom), 7.51 (d, J=8.5, 2H, arom).

REFERENCE EXAMPLE 41 3-(4-Chlorophenyl)-1,2,4-oxadiazole-5-carboxylicacid

(a) This product was prepared by a modification of the general proceduredescribed in Diana et al. J.Med.Chem. 1995, 38, 1355. A mixture of4-chlorobenzonitrile (5 g, 36.34 mmol), EtOH (90 mL), hydroxylaminehydrochloride (2.52 g, 36.34 mmol) and K₂ CO₃ (2.51 g, 18.17 mmol) wasrefluxed for 20 h. The reaction mixture was concentrated, cold water wasadded, and it was filtered and dried to give 4-chlorobenzoamidoxime as awhite solid (3.5 g, 56%). Next, this product (1.7 g, 10 mmol) was takenup in pyridine (34 mL) and treated with ethyl oxalyl chloride (2.22 mL,20 mmol) at 0° C. The reaction mixture was stirred for 1 h, then pouredinto pH 7 phosphate buffer, concentrated and partitioned between CHCl₃and water. The organic phase was washed with 10% aqueous NaHCO₃solution, dried over Na₂ SO₄, filtered, concentrated and purified byflash chromatography to give ethyl3-(4-chlorophenyl)-1,2,4-oxadiazole-5-carboxylate as an amorphous solid(2.14 g, 85%): ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.18 (dt, J_(t) =2.2,J_(d) =8.6, 2H, arom), 7.56 (dt, J_(t) =2.2, J_(d) =8.6, 2H, arom), 4.66(q, J=7.1, 2H, OCH₂), 1.57 (t, J=7.1, 3H, OCH₂ CH₃).

(b) This product was subjected to the hydrolysis procedure described inreference example 24 for 1 h to give the title compound as a whitesolid, which contained a small amount of the decarboxylated product: mp43°-44° C.; ¹ H NMR (300 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 7.63 (d, J=9, 2H,arom), 7.50 (d, J=9, 2H, arom).

REFERENCE EXAMPLE 42 5-(4-Chlorophenyl)-1,2,4-oxadiazole-3-carboxylicacid

(a) This product was prepared by a modification of the general proceduredescribed in Shimizu, T. et al. Bull.Chem.Soc.Jpn. 1985, 58, 2519. Amixture of 4-chlorobenzonitrile (1.7 g, 12.2 mmol), and diethylnitromalonate (2.5 g, 12.2 mmol) in dodecane (20 mL) was heated at 150°C. for 15 h. After the reaction was complete, the mixture was allowed tocool to room temperature and was then concentrated in vacuo. The residuewas purified by flash chromatography to yield ethyl5-(4-chlorophenyl)-1,2,4-oxadiazole-3-carboxylate as a light brownsolid: mp 88°-89° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.15 (dt, J_(t)=2.3, J_(d) =8.7, 2H, arom), 7.54 (dt, J_(t) =2.3, J_(d) =8.7, 2H,arom), 4.55 (q, J=7.1, 2H, OCH₂), 1.47 (t, J=7.1, 3H, OCH₂ CH₃).

(b) Following the hydrolysis procedure described in section b ofreference example 2 the title compound was obtained as a white solid,contaminated with a small amount of the decarboxylated product: ¹ H NMR(300 MHz, CDCl₃ +MeOH--d₄) δ (TMS) 8.11 (d, J=9, 2H, arom), 7.51 (d,J=9, 2H, arom).

REFERENCE EXAMPLE 432-(4-tert-Butylphenyl)-4-methylthiazole-5-carboxylic acid

(a) Following the procedure described in section a of reference example19 methyl 2-(4-tert-butylphenyl)-4-methylthiazole-5-carboxylate wasobtained as a colourless oil: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.89 (dt,J_(t) =2.2, J_(d) =8.6, 2H, arom), 7.46 (dt, J_(t) =2.2, J_(d) =8.6, 2H,arom), 3.89 (s, 3H, OMe), 2.78 (s, 3H, Me-thiazole), 1.35 (s, 9H, CMe₃).

(b) Following the hydrolysis procedure described in section b ofreference example 2 the title compound was obtained as a white solid: mp190°-193° C.; ¹ H NMR (300 MHz, MeOH--d₄) δ (MeOH) 7.89 (dt, J_(t) =2.2,J_(d) =8.6, 2H, arom), 7.53 (dt, J_(t) =2.2, J_(d) =8.6, 2H, arom), 2.72(s, 3H, Me-thiazole), 1.36 (s, 9H, CMe₃). Analysis calculated for C₁₅H₁₇ NO₂ S: C 65.43; H 6.22; N 5.09; S 11.64. Found: C 65.41; H 6.22; N4.92; S 10.84.

EXAMPLE 1 (1R,2R)-1-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1H-pyrazole-4-carboxamide

To a solution of(2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(340 mg, 1.26 mmol, prepared as described in J. Org. Chem., 1995, 60,3000-3012) in DMF (6 mL) was added 1-hydroxybenzotriazole (207 mg, 1.32mmol). Next, 1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid (280 mg,1.26 mmol, obtained in reference example 1) and DCC (272 mg, 1.32 mmol)were added and the mixture was stirred at room temperature for 18 h. Thereaction mixture was then cooled to 0° C. and the dicyclohexylureaformed was filtered, washed with CHCl₃ and the remaining solution wasevaporated to dryness and partitioned between 10% aqueous NaHCO₃solution and CHCl₃. The layers were separated and the organic phase wasdried over Na₂ SO₄, filtered and concentrated. The residue was purifiedby flash chromatography (hex: EtOAc 1:1 then 1:3) to afford the titleproduct, which was recrystallized from EtOAc: ether: hexane to yield awhite solid (560 mg, 94%): mp 212°-213° C.; ¹ H NMR (80 MHz, CDCl₃) δ(TMS) 8.39 (s, 1H, pyrazole), 8.02 (s, 1H, pyrazole), 7.9-7.2 (m, 7H,arom), 7.0-6.6 (m, 2H, arom), 6.43 (br d, J=9, 1H, NH), 5.35 (d, J=1.3,1H, OH), 5.06 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d,J=14.5, 1H, TrCH(H)), 1.02 (d, J=7, 3H, MeCH); α!^(D) =-106.3° (c 1,CHCl₃). Analysis calculated for C₂₂ H₁₉ ClF₂ N₆ O₂ : C 55.88; H 4.05; N17.77. Found: C 55.96; H 4.06; N 17.55.

EXAMPLE 2 (1R,2R)-1-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (referenceexample 2) the title compound was obtained as a white solid: mp154°-155° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.90 (s, 1H, triazole),7.79 (s, 2H, triazole, pyrazole), 7.6-7.2 (m, 5H, arom), 7.0-6.6 (m, 2H,arom), 6.37 (br d, J=9, 1H, NH), 5.35 (d, J=1.3, 1H, OH), 5.06 (d,J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H,TrCH(H)), 2.61 (s, 3H, Me-pyrazole), 1.02 (d, J=7, 3H, MeCH); α!^(D)=-91.4° (c 1, CHCl₃). Analysis calculated for C₂₃ H₂₁ ClF₂ N₆ O₂ : C56.74; H 4.35; N 17.26. Found: C 56.79; H 4.62; N 17.15.

EXAMPLE 3 (1R,2R)-1-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(11H-1,2,4-triazol-1-yl)propyl!-5-trifluoromethyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid thetitle compound was obtained as a white solid: mp 138°-139° C.; ¹ H NMR(80 MHz, CDCl₃) δ (TMS) 7.98 (s, 1H, triazole), 7.79 (s, 2H, triazole,pyrazole), 7.6-7.2 (m, 5H, arom), 7.0-6.6 (m, 2H, arom), 6.48 (br d,J=9, 1H, NH), 5.31 (d, J=1.3, 1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)),5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 1.02 (d, J=7, 3H,MeCH); α!^(D) =-103.6° (c 1, CHCl₃). Analysis calculated for C₂₃ H₁₈ N₆ClF₅ N₆ O₂ : C 51.07; H 3.35; N 15.54. Found: C 50.66; H 3.41; N 15.39.

EXAMPLE 4 (1R,2R)-1-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-propyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-chlorophenyl)-5-propyl-1H-pyrazole-4-carboxylic acid the titlecompound was obtained as an amorphous solid: ¹ H NMR (80 MHz, CDCl₃) δ(TMS) 7.88 (s, 1H, triazole), 7.79 (s, 2H, triazole, pyrazole), 7.6-7.2(m, 5H, arom), 7.0-6.6 (m, 2H, arom), 6.38 (br d, J=9, 1H, NH), 5.35 (d,3=1.3, 1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe),4.50 (d, J=14.5, 1H, TrCH(H)), 3.2-2.8 (m, 2H, Pr), 1.7-1.5 (m, 2H, Pr),1.02 (d, J=7, 3H, MeCH), 0.87 (t, 3H, Pr); α!^(D) =-79.5° (c 1, CHCl₃).Analysis calculated for C₂₅ H₂₅ ClF₂ N₆ O₂ : C 58.31; H 4.89; N 16.32.Found: C 58.14; H 5.14; N 16.36.

EXAMPLE 5 (1R,2R)-1-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-isopropyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-chlorophenyl)-5-isopropyl-1H-pyrazole-4-carboxylic acid (referenceexample 3) the title compound was obtained as an amorphous solid: mp85°-92° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.83 (s, 1H, pyrazole), 7.79(s, 2H, triazole), 7.6-7.2 (m, 5H, arom), 7.0-6.6 (m, 2H, arom), 6.41(br d, J=10, 1H, NH), 5.32 (d, J=1.3, 1H, OH), 5.05 (d, J=14.5, 1H,TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 3.4-3.1(m, 1H, CHMe₂), 1.38 (d, J=7, 6H, CHMe₂), 1.02 (d, J=7, 3H, MeCH);α!^(D) =-82.5° (c 1, CHCl₃). Analysis calculated for C₂₅ H₂₅ ClF₂ N₆O₂.1/2H₂ O: C 57.30; H 5.00; N 16.04. Found: C 57.04; H 5.27; N 15.73.

EXAMPLE 6 (1R,2R)-5-tertButyl-1-(4-chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using5-tertbutyl-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid (referenceexample 4) the title compound was obtained as a white solid: mp191°-192° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.80 (s, 2H, triazole),7.68 (s, 1H, pyrazole), 7.6-7.2 (m, 5H, arom), 7.0-6.6 (m, 2H, arom),6.45 (br d, J=10, 1H, NH), 5.31 (d, J=1.3, 1H, OH), 5.05 (d, J=14.5, 1H,TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 1.31 (s,9H, t-Bu), 1.02 (d, J=7, 3H, MeCH); α!^(D) =-92.0° (c 1, CHCl₃).Analysis calculated for C₂₆ H₂₇ ClF₂ N₆ O₂ : C 59.03; H 5.14; N 15.89.Found: C 59.36; H 5.66; N 15.87.

EXAMPLE 7 (1R,2R)-1-(4-Chlorophenyl)-5-cyclopropyl-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid(reference example 5) the title compound was obtained as a white solid:mp 181°-182° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.06 (s, 1H, pyrazole),7.79 (s, 2H, triazole), 7.49 (s, 4H, arom), 7.6-7.2 (m, 1H, arom),7.0-6.6 (m, 3H, arom, NH), 5.33 (d, J=1.3, 1H, OH), 5.05 (d, J=14.5, 1H,TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 2.2-1.8(m, 1H, c-prop), 1.3-1.0 (m, 2H, c-Pr), 1.04 (d, J=7, 3H, MeCH), 0.8-0.5(m, 2H, c-pr); α!^(D) =-112.6° (c 1, CHCl₃). Analysis calculated for C₂₅H₂₃ ClF₂ N₆ O₂ : C 58.54; H 4.52; N 16.38. Found: C 58.90; H 4.87; N16.27.

EXAMPLE 8 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using5-methyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid(reference example 6) the title compound was obtained as a white solid:mp 180°-181° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.02 (s, 1H), 7.9-7.2(m, arom), 7.0-6.6 (m, 2H, arom), 6.37 (br d, J=10, 1H, NH), 5.37 (d,J=1.3, 1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe),4.50 (d, J=14.5, 1H, TrCH(H)), 2.69 (s, 3H, Me-pyrazole), 1.04 (d, J=7,3H, MeCH); α!^(D) =-90.8° (c 1, CHCl₃). Analysis calculated for C₂₄ H₂₁F₅ N₆ O₂ : C 55.39; H 4.07; N 16.15. Found: C 55.57; H 4.27; N 16.01.

EXAMPLE 9 (1R,2R)-1-(4-Bromophenyl )-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (referenceexample 7) the title compound was obtained as a white solid: mp153°-154° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.91 (s, 1H, pyrazole),7.81 (s, 1H, triazole), 7.80 (s, 1H, triazole), 7.66 (d, J=8.7, 2H,arom), 7.4 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.32 (d, J=8.7, 2H,arom), 6.8-6.6 (m, 2H, arom), 6.35 (br d, J=9.5, 1H, NH), 5.36 (d,J=1.3, 1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe),4.53 (d, J=14.5, 1H, TrCH(H)), 2.63 (s, 3H, Me-pyrazole), 1.03 (d,J=6.8, 3H, MeCH); MS 306 and 308 (ethylaminoacyl group, C₁₃ H₁₃ BrN₃ O),263 and 265 (acyl group, C₁₁ H₈ BrN₂ O), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂N₃ O); α!^(D) =-86.8° (c 1, CHCl₃). Analysis calculated for C₂₃ H₂₁ BrF₂N₆ O₂ : C 51.99; H 3.98; N 15.82. Found: C 52.10; H 4.01; N 15.76.

EXAMPLE 10 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-trifluoromethyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using5-trifluoromethyl-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylicacid (reference example 8) the title compound was obtained as a whitesolid: mp 141°-143° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.02 (s, 1H),7.9-7.2 (m, arom), 7.0-6.4 (m, 3H, arom, NH), 5.31 (d, J=1.3, 1H, OH),5.05 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5,1H, TrCH(H)), 1.02 (d, J=7, 3H, MeCH); α!^(D) =-86.3° (c 1, CHCl₃).Analysis calculated for C₂₄ H₁₈ F₈ N₆ O₂ : C 50.18; H 3.16; N 14.63.Found: C 49.75; H 3.20; N 14.45.

EXAMPLE 11 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(2,4-difluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid the titlecompound was obtained as a white solid: mp 208°-209° C.; ¹ H NMR (80MHz, CDCl₃) δ (TMS) 7.93 (s, 1H, triazole), 7.78 (s, 2H, triazole,pyrazole), 7.6-7.0 (m, 3H, arom), 7.0-6.6 (m, 3H, arom), 6.35 (br d,J=9, 1H, NH), 5.34 (d, J=1.3, 1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)),5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 2.49 (s, 3H,Me-pyrazole), 1.02 (d, J=7, 3H, MeCH); α!^(D) =-89.6° (c 1, CHCl₃).Analysis calculated for C₂₃ H₂₀ F₄ N₆ O₂ : C 56.56; H 4.13; N 17.21.Found: C 56.88; H 4.36; N 16.83.

EXAMPLE 12 (1R,2R)-1-(3,5-Dichlorophenyl)-N-2-1,2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(3,5-dichlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (referenceexample 9) the title compound was obtained as a white solid: mp220°-221° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.92 (s, 1H, pyrazole),7.81 (s, 1H, triazole), 7.80 (s, 1H, triazole), 7.5-7.3 (m, 4H, arom),6.8-6.6 (m, 2H, arom), 6.36 (br d, J=9.5, 1H, NH), 5.36 (d, J=1.3, 1H,OH), 5.05 (d, J=14.5, 1H, TrCH(H)), 4.96 (br quint, 1=7, 1H, CHMe), 4.53(d, J=14.5, 1H, TrCH(H)), 2.68 (s, 3H, Me-pyrazole), 1.03 (d, J=6.8, 3H,MeCH); MS 296 and 298 (ethylaminoacyl group, C₁₃ H₁₂ Cl₂ N₃ O), 253 and255 (acyl group, C₁₁ H₇ Cl₂ N₂ O), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O);α!^(D) =-83.10° (c 1, CHCl₃). Analysis calculated for C₂₃ H₂₀ Cl₂ F₂ N₆O₂ : C 52.99; H 3.87; N 16.12. Found: C 53.58; H 4.08; N 15.90.

EXAMPLE 13 (1R,2R)-1-(2,6-Dichlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(2,6-dichlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (referenceexample 10) the title compound was obtained: mp 226°-227° C.; ¹ H NMR(300 MHz, CDCl₃) δ (TMS) 8.03 (s, 1H, pyrazole), 7.81 (s, 2H, triazole),7.6-7.3 (m, 4H, arom), 6.8-6.6 (m, 2H, arom), 6.42 (br d, J=9.5, 1H,NH), 5.38 (d, J=1.3, 1H, OH), 5.07 (d, J=14.5, 1H, TrCH(H)), 4.97 (brquint, J=7, 1H, CHMe), 4.57 (d, J=14.5, 1H, TrCH(H)), 2.44 (s, 3H,Me-pyrazole), 1.04 (d, J=6.8, 3H, MeCH); MS 296 and 298 (ethylaminoacylgroup, C₁₃ H₁₂ Cl₂ N₃ O), 253 and 255 (acyl group, C₁₁ H₇ Cl₂ N₂ O), 224(Tr--CH₂ COHAr, ClOH₈ F₂ N₃ O); α!^(D) =-80.3° (c 1, CHCl₃). Analysiscalculated for C₂₃ H₂₀ Cl₂ F₂ N₆ O₂ : C 52.99; H 3.87; N 16.12. Found: C53.29; H 3.91; N 15.93.

EXAMPLE 14 (1R,2R)-1-(2-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(2-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (referenceexample 11) the title compound was obtained as a white solid: mp232°-233° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.97 (s, 1H, pyrazole),7.81 (s, 2H, triazole), 7.6-7.3 (m, 5H, arom), 6.8-6.6 (m, 2H, arom),6.39 (br d, J=9.5, 1H, NH), 5.38 (d, J=1.5, 1H, OH), 5.07 (d, J=14.4,1H, TrCH(H)), 4.97 (br quint, J=7, 1H, CHMe), 4.57 (d, J=14.4, 1H,TrCH(H)), 2.48 (s, 3H, Me-pyrazole), 1.05 (d, J=6.8, 3H, MeCH); α!^(D)=-85.20 (c 1, CHCl₃). Analysis calculated for C₂₃ H₂₁ ClF₂ N₆ O₂ : C56.74; H 4.35; N 17.26. Found: C 56.87; H 4.56; N 17.03.

EXAMPLE 15 (1R,2R)-1-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-3,5-dimethyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-chlorophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (referenceexample 12) the title compound was obtained : mp 144°-145° C.; ¹ H NMR(80 MHz, CDCl₃) δ (TMS) 7.978 (s, 2H, triazole), 7.6-7.2 (m, 5H, arom),7.0-6.6 (m, 2H, arom), 6.28 (br d, J=10, 1H, NH), 5.35 (d, J=1.3, 1H,OH), 5.07 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d,J=14.5,1 H, TrCH(H)), 2.56 (s, 3H, Me-pyrazole), 2.54 (s, 3H,Me-pyrazole), 1.02 (d, J=7, 3H, MeCH); α!^(D) =-93.9° (c 1, CHCl₃).Analysis calculated for C₂₄ H₂₃ ClF₂ N₆ O₂ : C 57.55; H 4.63; N 16.78.Found: C 57.91; H 4.80; N 16.53.

EXAMPLE 16 (1R,2R)-5-Amino-1-(4-chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic acid (referenceexample 13) the title compound was obtained as a white solid: mp181°-182° C.; ² H NMR (80 MHz, CDCl₃) δ (TMS) 7.78 (s, 2H, triazole),7.69 (s, 1H, pyrazole), 7.50 (br 5, 4H, arom), 7.6-7.2 (m, 1H, arom),7.0-6.6 (m, 2H, arom), 6.15 (br d, J=9, 1H, NH), 5.55 (br s, 2H, NH₂),5.36 (s, 1H, OH), 5.06 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe),4.50 (d, J=14.5, 1H, TrCH(H)), 1.02 (d, J=7, 3H, MeCH); α!^(D) =-86.7°(c 1, CHCl₃). Analysis calculated for C₂₂ H₂₀ ClF₂ N₇ O₂ : C 54.16; H4.13; N 20.10. Found: C 54.28; H 4.35; N 19.76.

EXAMPLE 17 (1R,2R)-5-Amino-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using5-amino-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid(reference example 14) the title compound was obtained as a white solid:mp 208°-210° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.76 (m, 7H, triazole,arom, pyrazole), 7.6-7.3 (m, 1H, arom), 7.0-6.6 (m, 2H, arom), 6.18 (brd, J=9, 1H, NH), 5.6 (br s, 2H, NH₂), 5.37 (s, 1H, OH), 5.06 (d, J=14.5,1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 1.02(d, J=7, 3H, MeCH); α!^(D) =-69.6° (c 1, CHCl₃). Analysis calculated forC₂₃ H₂₀ F₅ N₇ O₂.2H₂ O: C 49.55; H 4.34; N 17.59. Found: C 49.33; H3.99; N 17.58.

EXAMPLE 18 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1-(3-trifluoromethylphenyl)-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using5-methyl-1-(3-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid(reference example 15) the title compound was obtained as a white solid:mp 146°-147° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.95 (s, 1H,pyrazole), 7.82 (s, 2H, triazole), 7.6-7.5 (m, 4H, arom), 7.40 (dt,J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 2H, arom), 6.41 (br d,J=9.5, 1H, NH), 5.37 (d, J=1.3, 1H, OH), 5.06 (d, J=14.5, 1H, TrCH(H)),4.96 (br quint, J=7, 1H, CHMe), 4.53 (d, J=14.5, 1H, TrCH(H)), 2.67 (s,3H, Me-pyrazole), 1.03 (d, J=6.8, 3H, MeCH); MS 296 (ethylaminoacylgroup, C₁₄ H₁₃ F₃ N₃ O), 253 (acyl group, C₁₂ H₈ F₃ N₂ O), 224 (Tr--CH₂COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =90.5° (c 1, CHCl₃). Analysis calculatedfor C₂₄ H₂₁ F₅ N₆ O₂ : C 55.39; H 4.07; N 16.15. Found: C 55.33; H 3.97;N 16.12.

EXAMPLE 19 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using5-methyl-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carboxylic acid(reference example 16) the title compound was obtained as a white solid:mp 134°-135° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.93 (s, 1H,pyrazole), 7.815 (s, 1H, triazole), 7.810 (s, 1H, triazole), 7.6-7.3 (m,5H, arom), 6.8-6.6 (m, 2H, arom), 6.38 (br d, J=9.5, 1H, NH), 5.37 (d,J=1.3, 1H, OH), 5.07 (d, J=14.5, 1H, TrCH(H)), 4.97 (br quint, J=7, 1H,CHMe), 4.54 (d, J=14.5, 1H, TrCH(H)), 2.65 (s, 3H, Me-pyrazole), 1.04(d, J=6.8, 3H, MeCH); MS 312 (ethylaminoacyl group, C₁₄ H₁₃ F₃ N₃ O₂),269 (acyl group, C₁₂ H₈ F₃ N₂ O₂), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O);α!^(D) =83.1° (c 1, CHCl₃). Analysis calculated for C₂₄ H₂₁ F₅ N₆ O₃ : C53.73; H 3.95; N 15.67. Found: C 53.99; H 3.94; N 15.46.

EXAMPLE 20 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (referenceexample 17) the title compound was obtained: mp 176°-177° C.; ¹ H NMR(300 MHz, CDCl₃) δ (TMS) 7.89 (s, 1H, pyrazole), 7.81 (s, 2H, triazole),7.41 (dt, J_(d) =0 6.5, J_(t) =8.8, 1H, arom), 7.33 (dt, J_(t) =2.5,J_(d) =6.6, 2H, arom), 7.02 (dt, J_(t) =2.5, J_(d) =6.6, 2H, arom),6.8-6.6 (m, 2H, arom), 6.35 (br d, J=9.5, 1H, NH), 5.37 (d, J=1.3, 1H,OH), 5.07 (d, J=14.5, 1H, TrCH(H)), 4.97 (br quint, J=7, 1H, CHMe), 4.55(d, J=14.5, 1H, TrCH(H)), 3.88 (s, 3H, OMe), 2.59 (s, 3H, Me-pyrazole),1.04 (d, J=6.8, 3H, MeCH); MS 258 (ethylaminoacyl group, C₁₄ H₁₆ N₃ O₂),215 (acyl group, C₁₂ H₁₁ N₂ O₂), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O);α!^(D) =-90.3° (c 1, CHCl₃). Analysis calculated for C₂₄ H₂₄ F₂ N₆ O₃ :C 59.75; H 5.01; N 17.42. Found. C 59.88; H 4.91; N 17.30.

EXAMPLE 21 (1R,2R)-1-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!pyrrole-3-carboxamide

Following a similar procedure to that described in example 1 but using1-(4-chlorophenyl)pyrrole-3-carboxylic acid (prepared as described inFabis et al, Org.Prep.Proced.Int. 1995, 27, 236) the title compound wasobtained as an amorphous solid: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 7.79 (s,2H, triazole), 7.63 (t, J=2, 1H, pyrrole), 7.6-7.3 (m, 5H, arom), 7.02(t, J=2, 1H, pyrrole), 7.0-6.6 (m, 2H, arom), 6.63 (t, J=2, 1H,pyrrole), 6.35 (br d, 1H, NH), 5.36 (d, J=1.3, 1H, OH), 5.06 (d, J=14.5,1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 1.03(d, J=7, 3H, MeCH); α!^(D) =-95.2° (c 1, CHCl₃). Analysis calculated forC₂₃ H₂₀ ClF₂ N₅ O₂ : C 58.54; H 4.27; N 14.84. Found: C 58.42; H 4.26; N14.65.

EXAMPLE 22 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!thiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-chlorophenyl)thiazole-5-carboxylic acid (reference example 18) thetitle compound was obtained as a white solid: mp 194-195° C.; ¹ H NMR(300 MHz, CDCl₃) δ (TMS) 8.25 (s, 1H, thiazole), 7.93 (dt, J_(t) =2,J_(d) =9, 2H, arom), 7.81 (s, 1H, triazole), 7.79 (s, 1H, triazole),7.45 (dt, J_(t) =2, J_(d) =9, 2H, arom), 7.39 (dt, J_(d) =6.5, J_(t)=8.8, 1H, arom), 6.8-6.6 (m, 2H, arom), 6.55 (br d, J=9.3, 1H, NH), 5.40(d, J=1.6, 1H, OH), 5.03 (d, J=14.5, 1H, TrCH(H)), 4.95 (br quint, J=7,1H, CHMe), 4.52 (d, J=14.5, 1H, TrCH(H)), 1.04 (d, J=6.8, 3H, MeCH);HPLC-MS 265 and 267 (ethylaminoacyl group, C₁₂ H₁₀ ClN₂ OS), 222 (acylgroup, C₁₀ H₅ ClNOS), 224 (Tr--CH₂ COHAr, C₁₀ OH₈ F₂ N₃ O); α!^(D)=-105.6° (c 1, CHCl₃). Analysis calculated for C₂₂ H₁₈ ClF₂ N₅ O₂ S: C53.94; H 3.70; N 14.29; S 6.54. Found: C 54.04; H 3.78; N 14.16; S 6.12.

EXAMPLE 23 (1R,2R)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methyl-2-phenylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using4-methyl-2-phenylthiazole-5-carboxylic acid (reference example 19) thetitle compound was obtained as an amorphous solid: ¹ H NMR (300 MHz,CDCl₃) δ (TMS) 8.0-7.9 (m, 2H, arom), 7.81 (s, 1H, triazole), 7.79 (s,1H, triazole), 7.5-7.4 (m, 3H, arom), 7.38 (dt, J_(d) =6.5, J_(t) =8.8,1H, arom), 6.9-6.7 (m, 2H, arom), 6.40 (br d, J=9.5, 1H, NH), 5.38 (d,J=1.3, 1H, OH), 5.05 (d, J=14.2, 1H, TrCH(H)), 4.93 (br quint, J=7, 1H,CHMe), 4.53 (d, J=14.2, 1H, TrCH(H)), 2.82 (s, 3H, Me-thiazole), 1.03(d, J=6.8, 3H, MeCH); 60 !^(D) =-114.2° (c 1, CHCl₃). Analysiscalculated for C₂₃ H₂₁ F₂ N₅ O₂ S: C 58.84; H 4.51; N 14.92; S 6.83.Found: C 58.59; H 4.78; N 15.02; S 6.50.

EXAMPLE 24 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(-1,2,4-triazol-1-yl)propyl!-4-methyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using4-methyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxylic acid andrecrystallizing the product obtained from DMF-H₂ O, the title compoundwas obtained as a white solid: mp 79°-82 ° C.; ¹ H NMR (80 MHz, CDCl₃)δ(TMS) 8.1 (s, 1H, triazole), 8.03 (s, 1H, triazole), 7.78 (br s, arom),7.66 (s, arom), 7.6-7.2 (1H, arom), 7.0-6.6 (m, 2H, arom), 6.4 (br d,J=9, 1H, NH), 5.38 (d, J=1.3, 1H, OH), 5.06 (d, J=14.5, 1H, TrCH(H)),5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 2.82 (s, 3H,Me-thiazole), 1.02 (d, J=7, 3H, MeCH); α!^(D) =-103.2° (c 1, CHCl₃).Analysis calculated for C₂₄ H₂₀ F₅ N₅ O₂ S: C 53.63; H 3.75; N 13.03; S5.96. Found: C 53.77; H 3.97; N 13.51; S 5.51.

EXAMPLE 25 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-chlorophenyl)-4-methylthiazole-5-carboxylic acid (reference example20) the title compound was obtained as a white solid: mp 159°-160° C.; ¹H NMR (80 MHz, CDCl₃) δ (TMS) 8.0-7.8 (m, 4H, arom, triazole), 7.6-7.2(m, 3H, arom), 7.0-6.6 (m, 2H, arom), 6.4 (br d, J=10, 1H, NH), 5.37 (d,J=1.3, 1H, OH), 5.06 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe),4.50 (d, J=14.5, 1H, TrCH(H)), 2.80 (s, 3H, Me-thiazole), 1.02 (d, J=7,3H, MeCH); MS 281 and 283 (ethylaminoacyl group, C₁₃ H₁₄ ClN₂ OS), 236and 238 (acyl group, C₁₁ H₇ ClNOS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O);α!^(D) =-117.1° (c 1, CHCl₃). Analysis calculated for C₂₃ H₂₀ ClF₂ N₅ O₂S: C 54.82; H 4.00; N 13.90; S 6.36. Found: C 55.13; H 3.93; N 13.86; S6.09.

EXAMPLE 26 (1R,2R)-2-(4-Bromophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-bromophenyl)-4-methylthiazole-5-carboxylic acid (reference example21) the title compound was obtained as a white solid: mp 165°-166° C.; ¹H NMR (80 MHz, CDCl₃) δ (TMS) 7.71 (d, J=7.5, 2H, arom), 7.79 (s, 2H,triazole), 7.57 (d, J=7.5, 2H, arom), 7.6-7.2 (m, 1H, arom), 7.0-6.6 (m,2H, arom), 6.43 (br d, J=10, 1H, NH), 5.39 (d, J=1.3, 1H, OH), 5.05 (d,J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1 H, CHMe), 4.50 (d, J=14.5, 1H,TrCH(H)), 2.80 (s, 3H, Me-thiazole), 1.02 (d, J=7, 3H, MeCH); MS 323 and325 (ethylaminoacyl group, C₁₃ H₁₂ BrN₂ OS), 280 and 282 (acyl group,C₁₁ H₇ BrNOS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-108.7° (c1, CHCl₃). Analysis calculated for C₂₃ H₂₀ BrF₂ N₅ O₂ S: C 50.37; H3.68; N 12.77; S 5.85. Found: C 50.61; H 3.66; N 12.81; S 5.62.

EXAMPLE 27 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methyl-2-(4-trifluoromethoxyphenyl)thiazole-5carboxamide

Following a similar procedure to that described in example 1 but using4-methyl-2-(4-trifluoromethoxyphenyl)thiazole-5-carboxylic acid(reference example 22) the title compound was obtained as an amorphoussolid: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.01 (dt, J_(t) =2, J_(d) =9,2H, arom), 7.83 (s, 1H, triazole), 7.81 (s, 1H, triazole), 7.39 (dt,J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.32 (d, J=9, 2H, arom), 6.8-6.6 (m,2H, arom), 6.44 (br d, J=9.5, 1H, NH), 5.40 (d, J=1.3, 1H, OH), 5.06 (d,J=14.5, 1H, TrCH(H)), 4.95 (br quint, J=7, 1H, CHMe), 4.53 (d, J=1 4.5,1H, TrCH(H)), 2.83 (s, 3H, Me-thiazole), 1.04 (d, J=6.8, 3H, MeCH); MS329 (ethylaminoacyl group, C₁₄ H₁₂ F₃ N₂ O₂ S), 286 (acyl group, C₁₂ H₇F₃ NO₂ S), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-105.4° (c 1,CHCl₃). Analysis calculated for C₂₄ H₂₀ F₅ N₅ O₃ S: C 52.08; H 3.64; N12.65; S 5.79. Found: C 52.27; H 3.88; N 12.26; S 5.40.

EXAMPLE 28 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methyl-2-4-(2,2,3,3-tetrafluoropropoxy)phenyl!thiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using4-methyl-2- 4-(2,2,3,3-tetrafluoropropoxy)phenyl! thiazole-5-carboxylicacid (reference example 23) the title compound was obtained as anamorphous solid: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.95 (dt, J_(t) =2,J_(d) =9, 2H, arom), 7.82 (s, 1H, triazole), 7.80 (s, 1H, triazole),7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.02 (dt, J_(t) =2, J_(d)=9, 2H, arom), 6.8-6.6 (m, 2H, arom), 6.41 (br d, J=9.5, 1H, NH), 6.08(tt, J=4.7, J=53, 1H, CF₂ H), 5.39 (d, J=1.3, 1H, OH), 5.06 (d, J=14.5,1H, TrCH(H)), 4.95 (br quint, J=7, 1H, CHMe), 4.53 (d, J=14.5, 1H,TrCH(H)), 4.35 (tt, J=1.3, J=12, 2H, OCH₂), 2.81 (s, 3H, Me-thiazole),1.03 (d, J=6.8, 3H, MeCH); MS 375 (ethylaminoacyl group, C₁₆ H₁₅ F₄ N₂O₂ S), 332 (acyl group, C₁₄ H₁₀ F₄ NO₂ S), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂N₃ O); α!^(D) =-85.7° (c 1, CHCl₃). Analysis calculated for C₂₆ H₂₃ F₆N₅ O₃ S: C 52.09; H 3.87; N 11.68; S 5.35. Found: C 52.23; H 3.60; N11.62: S 5.24.

EXAMPLE 29 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5carboxamide

Following a similar procedure to that described in example 1 but using2-(4-cyanophenyl)-4-methylthiazole-5-carboxylic acid (reference example24) the title compound was obtained as a white solid: mp 109°-111° C.; ¹H NMR (300 MHz, CDCl₃) δ (TMS) 8.07 (d, J=8.3, 2H, arom), 7.81 (s, 1H,triazole), 7.79 (s, 1H, triazole), 7.75 (d, J=8.3, 2H, arom), 7.37 (dt,J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 2H, arom), 6.46 (br d,J=9.5, 1H, NH), 5.40 (s, 1H, OH), 5.03 (d, J=14.5, 1H, TrCH(H)), 4.94(br quint, J=7, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 2.83 (s, 3H,Me-thiazole), 1.02 (d, J=6.8, 3H, MeCH); MS 270 (ethylaminoacyl group,C₁₄ H₁₂ N₃ OS), 227 (acyl group, C₁₂ H₇ N₂ OS), 224 (Tr--CH₂ COHAr, C₁₀H₈ F₂ N₃ O); α!^(D) =-120.80 (c 1, CHCl₃). Analysis calculated for C₂₄H₂₀ F₂ N₆ O₂ S: C 58.29; H 4.08; N 16.99; S 6.48 Found: C 57.83; H 3.96;N 16.70; S 6.16.

EXAMPLE 30 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide,oxalate

To a solution of (1R,2R)-2-(4-cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide (obtained in example 29) in EtOH was added 2equivalents of oxalic acid and some diethyl ether. The solution wascooled to -20° C. and the precipitate formed was collected by filtrationand dried to give the title compound as a white solid: mp 104°-108° C.;¹ H NMR (300 MHz, MeOH--d₄) δ (TMS) 8.28 (s, 1H, triazole), 8.14 (d,J=8.3, 2H, arom), 8.1-7.9 (m, 1H), 7.84 (d, J=8.3, 2H, arom), 7.73 (s,1H, triazole), 7.37 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.0-6.9 (m,1H, arom), (6.9-6.8 (m, 1H, arom), 5.1-4.9 (m, 2H, TrCH(H), CHMe), 4.59(d, J=14.5, 1H, TrCH(H)), 2.73 (s, 3H, Me-thiazole), 1.05 (d, J=6.8, 3H,MeCH); α!^(D) =-72° (c 1, MeOH). Analysis calculated for C₂₄ H₂₀ F₂ N₆O₂ S.C₂ H₄ O₂.1/2H₂ O: C 52.61; H 3.90; N 14.16; S 5.39. Found: C 52.74;H 3.80; N 13.88; S 5.01.

EXAMPLE 31 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide,methane-sulfonate

To a solution of (1R,2R)-2-(4-cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide(obtained in example 29) in MeOH was added 2 equivalents ofmethanesulfonic acid diluted in MeOH. The solution was cooled to 0° C.and the precipitate formed was collected by filtration and dried to givethe title compound as white needles: mp 126°-138° C.; ¹ H NMR (300 MHz,DMSO--d₆) δ (DMSO) 8.55 (s, 1H, triazole), 8.15 (d, J=9.2, 1H, NH), 8.13(d, J=8.3, 2H, arom), 7.98 (d, J=8.3, 2H, arom), 7.87 (s, 1H, triazole),7.30 (br q, J=8.5, 1H, arom), 7.20 (ddd, J=2.4, J=9.2, J=11.8, 1H,arom), 6.92 (dt, J_(d) =2.4, J_(t) =8.5, 1H, arom), 4.9-4.8 (m, 2H,TrCH(H), CHMe), 4.54 (d, J=14.5, 1H, TrCH(H)), 2.68 (5, 3H,Me-thiazole), 2.38 (s, 3H, MeSO₃ H), 0.93 (d, J=6.8, 3H, MeCH); α!^(D)=-71° (c 1, DMF). Analysis calculated for C₂₄ H₂₀ F₂ N₆ O₂ S.CH₄ O₃ S.H₂O: C 49.34; H 4.31; N 13.81; S 10.53. Found: C 49.35; H 4.11; N 13.72; S10.30.

EXAMPLE 32 (1R,2R)-2-(4-Carbamoylphenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

To a solution of NH₄ OH in a H₂ O--THF mixture was added(1R,2R)-2-(4-cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide methanesulfonate (0.5 g, 0.84 mmol, obtained inexample 31). The mixture was refluxed for 2 days, then was concentratedand the aqueous residue was extracted with CHCl₃. The organic layer wasseparated, dried over Na₂ SO₄, filtered and the filtrate wasconcentrated to a solid (0.53 g). This was purified by flashchromatography to give the title compound as a white solid: 133°-135°C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.98 (d, J=8.3, 2H, arom), 7.87 (d,J=8.3, 2H, arom), 7.81 (s, 1H, triazole), 7.71 (s, 1H, triazole), 7.40(dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 2H, ) arom), 6.57(br d, J=9.5, 1H, NH), 6.27 (br s, 2H, NH₂), 5.63 (s, 1H, OH), 5.05 (d,J=14.5, 1H, TrCH(H)), 4.98 (br quint, J=7, 1H, CHMe), 4.57 (d, J=14.5,1H, TrCH(H)), 2.81 (s, 3H, Me-thiazole), 1.05 (d, J=6.8, 3H, MeCH); MS288 and 289 (ethylaminoacyl group, C₁₄ H₁₅ N₃ O₂ S), 245 (acyl group,C₁₂ H₉ N₂ O₂ S), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-74.5° (c1, MeOH). Analysis calculated for C₂₄ H₂₂ F₂ N₆ O₃ S: C 56.24; H 4.33; N16.40; S 6.26. Found: C 55.90; H 4.64; N 15.29; S 5.62.

EXAMPLE 33 (1R,2R)-2- 2-(4-Chlorophenyl)-4-methylthiazol-5-yl!-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2-2-(4-chlorophenyl)-4-methylthiazol-5-yl!-4-methylthiazole-5-carboxylicacid (reference example 25) the title compound was obtained as a yellowsolid: mp 110°-114° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.92 (dt, J_(t)=2, J_(d) =9, 2H, arom), 7.81 (s, 1H, triazole), 7.79 (s, 1H, triazole),7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.32 (dt, J_(t) =2, J_(d)=9, 2H, arom), 6.8-6.6 (m, 2H, arom), 6.42 (br d, J=9.5, 1H, NH), 5.40(d, J=1.1, 1H, OH), 5.05 (d, J=14.3, 1H, TrCH(H)), 4.95 (br quint, J=7,1H, CHMe), 4.52 (d, J=14.3, 1H, TrCH(H)), 2.80 (s, 3H, Me-thiazole),2.78 (s, 3H, Me-thiazole), 1.03 (d, J=6.8, 3H, MeCH); HPLC-MS 376 and378 (ethylaminoacyl group, C₁₇ H₁₅ ClN₃ OS₂), 333 and 335 (acyl group,Cl₅ H₁₀ ClN₂ OS₂), 224 (Tr--CH₂ COHAr, C₁ OH₈ F₂ N₃ O); α!^(D) =-98° (c1, CHCl₃). Analysis calculated for C₂₇ H₂₃ ClF₂ N₆ O₂ S₂ : C 53.95; H3.86; N 13.98; S 10.67. Found: C 54.21; H 4.02; N 13.60; S 9.78.

EXAMPLE 34 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-trifluoromethylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-chlorophenyl)-4-trifluoromethylthiazole-5-carboxylic acid(reference example 26), the title compound was obtained as a whitesolid: mp 78°-79° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.91 (dt, J_(t)=2.5, J_(d) =8.5, 2H, arom), 7.81 (s, 1H, triazole), 7.79 (s, 1H,triazole), 7.48 (dt, J_(d) =2.5, J_(t) =8.5, 2H, arom), 7.39 (dt, J_(d)=6.5, J_(t) =8.8, 1H, arom), 6.87 (br d, J=9.0, 1H, NH), 6.8-6.6 (m, 2H,arom), 5.38 (br s, 1H, OH), 5.01 (d, J=14.2, 1H, TrCH(H)), 4.91 (brquint, J=7, 1H, CHMe), 4.51 (d, J=14.2, 1H, TrCH(H)), 1.02 (d, J=6.8,3H, MeCH); α!^(D) =-88.8° (c 1, CHCl₃). Analysis calculated for C₂₃ H₁₇ClF₅ N₅ O₂ S: C 49.51; H 3.07; N 12.55; S 5.75. Found: C 49.86; H 3.08;N 12.36; S 5.38.

EXAMPLE 35 (1R,2R)-N-2-(24-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-trifluoromethyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using4-trifluoromethyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxylic acid(reference example 27), the title compound was obtained as a whitesolid: mp 83°-86° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.12 (d, J=8.1,2H, arom), 7.84 (5, 1H, triazole), 7.80 (s, 1H, triazole), 7.77 (d,J=8.1, 2H, arom), 7.38 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.95 (brd, J=9.0, 1H, NH), 6.8-6.6 (m, 2H, arom), 5.42 (d, J=1.6, 1H, OH), 5.03(d, J=14.2, 1H, TrCH(H)), 4.96 (br quint, J=7, 1H, CHMe), 4.51 (d,J=14.2, 1H, TrCH(H)), 1.04 (d, J=6.8, 3H, MeCH); α!^(D) =-79° (c 1,CHCl₃). Analysis calculated for C₂₄ H₁₇ F₈ N₅ O₂ S: C 48.74; H 2.90; N11.84; S 5.42. Found: C 49.16; H 3.19; N 11.47; S 5.03.

EXAMPLE 36 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-trifluoromethylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-cyanophenyl)-4-trifluoromethylthiazole-5-carboxylic acid (referenceexample 28), the title compound was obtained as a white solid: mp101°-108° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.13 (d, J=8.1, 2H,arom), 7.86 (s, 1H, triazole), 7.83 (d, J=8.1, 2H, arom), 7.83 (s, 1H,triazole), 7.40 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.98 (br d,J=9.0, 1H, NH), 6.8-6.6 (m, 2H, arom), 5.44 (d, J=1.6, 1H, OH), 5.05 (d,J=14.2, 1H, TrCH(H)), 4.96 (br quint, J=7, 1H, CHMe), 4.55 (d, J=14.2,1H, TrCH(H)), 1.07 (d, J=6.8, 3H, MeCH); α!^(D) =-79.9° (c 1, CHCl₃).Analysis calculated for C₂₄ H₁₇ F₅ N₆ O₂ S: C 52.56; H 3.12; N 15.32; S5.85. Found: C 51.98; H 3.51; N 11.29; S 5.16.

EXAMPLE 37 (1R,2R)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-4-(1H-tetrazol-5yl)phenyl!-4-trifluoromethylthiazole-5-carboxamide,hydrochloride

The compound obtained in the previous example (400 mg, 0.73 mmol) wastreated with sodium azide (143 mg, 2.18 mmol) and triethylammoniumhydrochloride (151 mg, 1.09 mmol) in NMP (5 mL) at 150° C. for 2 h. Themixture was cooled to room temperature, H₂ O was added and it was madeacidic with 6N HCl. A creamy solid (350 mg) was obtained, which wasrecrystallized from isopropanol to give the title compound as a creamysolid: mp>250° C.; ¹ H NMR (300 MHz, MeOH--d₄) δ (MeOH--d₄) 9.32 (s, 1H,triazole), 8.39 (s, 1H, triazole), 8.28 (d, J=8.8, 2H, arom), 8.24 (d,J=8.8, 2H, arom), 7.36 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.06(ddd, J=2.4, J=8.7, J=11.5, 1H, arom), 6.90 (dt, J_(d) =2.1, J_(t) =8.0,1H, arom), 5.13 (d, J=14.3, 1H, TrCH(H)), 5.01 (q, J=7, 1H, CHMe), 4.77(d, J=14.3, 1H, TrCH(H)), 1.10 (d, J=7, 3H, MeCH); DIP/MS 367(ethylaminoacyl group, C₁₄ H₁₀ F₃ N₆ OS), 324 (acyl group, C₁₂ H₅ F₃ N₅OS), 224 (Tr--CH₂ COHAr, ClOH₈ F₂ N₃ O). Analysis calculated for C₂₄ H₁₈F₅ N₉ O₂ S.HCl.H₂ O: C 44.62; H 3.28; N 19.51; S 4.96. Found: C 44.12; H2.89; N 19.01; S 4.71.

EXAMPLE 38 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-4-(2-methyl-2H-tetrazol-5-yl)phenyl!-4-trifluoromethylthiazole-5-carboxamide

The compound obtained in the preceding example (162 mg, 0.27 mmol) wastreated with methyl iodide (48 mg, 0.34 mmol) and K₂ CO₃ (38 mg, 0.28mmol) in DMF (2 mL) at 25° C. for 2 h. The reaction mixture was thenevaporated to dryness, and the residue partitioned between H₂ O andCHCl₃. The organic phase was separated, dried and concentrated. Theresidue was flash chromatographed to afford mainly the title compound(38 mg) as a white solid: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.29 (d,J=8.3, 2H, arom), 8.13 (d, J=8.3, 2H, arom), 7.84 (s, 1H, triazole),7.81 (s, 1H, triazole), 7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom),6.91 (br d, J=9.0, 1 H, NH), 6.8-6.6 (m, 2H, arom), 5.41 (d, J=1.6, 1H,OH), 5.05 (d, J=14.2, 1H, TrCH(H)), 4.94 (br quint, J=7, 1H, CHMe), 4.55(d, J=14.2, 1H, TrCH(H)), 4.45 (s, 3H, Me-tetrazol), 1.05 (d, J=6.8, 3H,MeCH); DIP/MS 381 (ethylaminoacyl group, C₁₅ H₁₂ F₃ N₆ OS), 338 (acylgroup, C₁₃ H₁₇ F₃ N₅ OS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O).

EXAMPLE 39 (1R,2R)-2- (4-Chlorophenoxy)methyl!-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5carboxamide

Following a similar procedure to that described in example 1 but using2- (4-chlorophenoxy)methyl!-4-methylthiazole-5-carboxylic acid(reference example 29) the title compound was obtained as a white solid:mp 134°-135° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.80 (s, 1H,triazole), 7.77 (s, 1H, triazole), 7.36 (dt, J_(d) =6.5, J_(t) =8.8, 1H,arom), 7.28 (dt, J_(t) =2, J_(d) =9, 2H, arom), 6.93 (dt, J_(t) =2,J_(d) =9, 2H, arom), 6.8-6.6 (m, 2H, arom), 6.35 (br d, J=9.5, 1H, NH),5.34 (d, J=1.3, 1H, OH), 5.30 (s, 2H, CH₂ O), 5.02 (d, J=14.3, 1H,TrCH(H)), 4.91 (br quint, J=7, 1H, CHMe), 4.48 (d, J=14.3, 1H, TrCH(H)),2.76 (s, 3H, Me-thiazole), 0.99 (d, J=6.8, 3H, MeCH); GC/MS 309 and 310(ethylaminoacyl group, C₁₄ H₁₄ ClN₂ O₂ S), 266 and 268 (acyl group, C₁₂H₉ ClNO₂ S), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-94° (c 1,CHCl₃). Analysis calculated for C₂₄ H₂₂ ClF₂ N₅ O₃ S: C 53.98; H 4.15; N13.12; S 6.00 Found: C 54.04; H 4.48; N 12.35; S 5.27.

EXAMPLE 40 (1R,2R)-2- N-(4-Chlorophenyl)amino!-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2- N-(4-chlorophenyl)amino!-4-methylthiazole-5-carboxylic acid(reference example 30) the title compound was obtained as a whiteamorphous solid: HPLC-MS 295 and 267 (ethylaminoacyl group, C₁₃ H₁₄ ClN₃OS), 251 and 253 (acyl group, C₁₁ H₈ ClN₂ OS), 224 (Tr--CH₂ COHAr, C₁₀H₈ F₂ N₃ O).

EXAMPLE 41 (1R,2R)-2-(4-Chlorophenoxy)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

(a) Following a similar procedure to that described in example 1 butusing 2-bromo-4-methylthiazole-5-carboxylic acid (obtained as describedin Singh, J.M. J.Med.Chem. 1969, 12, 1553), (1R,2R)-2-bromo-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methyl-thiazole-5-carboxamide was obtained as a whitesolid: mp 155°-163° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.81 (s, 1H,triazole), 7.78 (s, 1H, triazole), 7.35 (dt, J_(d) =6.5, J_(t) =8.8, 1H,arom), 6.8-6.6 (m, 2H, arom), 6.36 (br d, J=9.5, 1H, NH), 5.4 (br s, 1H,OH), 5.00 (d, J=14.2, 1H, TrCH(H)), 4.90 (br quint, J=7, 1H, CHMe), 4.46(d, J=14.2, 1H, TrCH(H)), 2.74 (s, 3H, Me-thiazole), 0.99 (d, J=6.8, 3H,MeCH); α!^(D) =-97.8° (c 1, CHCl₃). Analysis calculated for C₁₇ H₁₆ BrF₂N₅ O₂ S: C 43.23; H 3.41; N 14.83: S 6.79. Found: C 43.23; H 3.64; N14.58; S 6.29.

(b) To a solution of the product obtained in section (a) (375 mg, 0.79mmol) in N-methylpyrrolidone (5 mL) was added 4-chlorophenol (117 mg,0.91 mmol) and anhydrous K₂ CO₃ (109 mg, 0.79 mmol). The mixture wasstirred at 130° C. for 18 h and then water and EtOAc were added. Theorganic phase was separated and the aqueous residue was extracted withEtOAc. The combined organic extracts were dried over Na₂ SO₄,concentrated and purified by flash chromatography to give the titlecompound as an amorphous solid (159 mg): ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 7.80 (s, 1H, triazole), 7.77 (s, 1H, triazole), 7.41 (d, J=9, 2H,arom), 7.36 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.25 (d, J=9, 2H,arom), 6.8-6.6 (m, 2H, arom), 6.20 (br d, J=9.5, 1H, NH), 5.33 (d,J=1.5, 1H, OH), 5.00 (d, J=14.2, 1H, TrCH(H)), 4.91 (br quint, J=7, 1H,CHMe), 4.46 (d, J=14.2, 1H, TrCH(H)), 2.62 (s, 3H, Me-thiazole), 0.98(d, J=6.8, 3H, MeCH); GC--MS 295 and 297 (ethylaminoacyl group, C₁₃ H₁₂ClN₂ O₂ S), 252 and 254 (acyl group, C₁₁ H₇ ClNO₂ S), 224 (Tr--CH₂COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-93° (c 1, CHCl₃).

EXAMPLE 42 (1R,2R)-2-(4-Chlorobenzenesulfonyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

Following the procedure described in example 41 but using the sodiumsalt of 4-chlorobenzenesulfinic acid (obtained as described inOrg.Synth.Coll.Vol IV, 674, from 4-chlorobenzenesulfonyl chloride andsodium sulfite) instead of the mixture of 4-chlorophenol and K₂ CO₃, thetitle compound was obtained as a white amorphous solid: ¹ H NMR (300MHz, CDCl₃) δ (TMS) 8.04 (dt, J_(t) =1.9, J_(d) =8.7, 2H, arom), 7.81(s, 1H, triazole), 7.76 (s, 1H, triazole), 7.56 (dt, J_(t) =1.9, J_(d)=8.7, 2H, arom), 7.34 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.8-6.6(m, 2H, arom), 6.20 (br d, J=9.5, 1H, NH), 5.41 (d, J=1.5, 1H, OH), 4.97(d, J=14.2, 1H, TrCH(H)), 4.86 (br quint, J=7, 1H, CHMe), 4.42 (d,J=14.2, 1H, TrCH(H)), 2.74 (s, 3H, Me-thiazole), 0.99 (d, J=6.8, 3H,MeCH);GC--MS 343 and 345 (ethylaminoacyl group, C₁₃ H₁₂ ClN₂ O₃ S₂), 300and 302 (acyl group, C₁₁ H₇ ClNO₃ S₂), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃O).

EXAMPLE 43 (1R,2R)-5-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-methylfuran-3-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)-2-methylfuran-3-carboxylic acid the title compoundwas obtained as a white solid: mp 189°-190° C.; ¹ H NMR (300 MHz, CDCl₃)δ (TMS) 7.80 (s, 1H, triazole), 7.79 (s, 1H, triazole), 7.59 (dt, J_(t)=2, J_(d) =8.4, 2H, arom), 7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom),7.37 (dt, J_(t) =2, J_(d) =8.4, 2H, arom), 6.8-6.6 (m, 2H, arom), 6.27(s, 1H, furan), 6.29 (br d, J=9.5, 1H, NH), 5.35 (s, 1H, OH), 5.04 (d,J=14.2, 1H, TrCH(H)), 4.93 (br quint, J=7, 1H, CHMe), 4.51 (d, J=14.2,1H, TrCH(H)), 2.71 (s, 3H, Me-furan), 1.01 (d, J=6.8, 3H, MeCH); HPLC-MS262 and 264 (ethylaminoacyl group, C₁₄ H₁₃ ClNO₂), 219 and 221 (acylgroup, C₁₂ H₈ ClO₂), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D)=-131.2° (c 1, CHCl₃). Analysis calculated for C₂₄ H₂₁ ClF₂ N₄ O₃ : C59.20; H 4.35; N 11.51. Found: C 59.22; H 4.34; N 11.58.

EXAMPLE 44 (1R,2R)-5-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-trifluoromethylfuran-3-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)-2-trifluoromethylfuran-3-carboxylic acid the titlecompound was obtained as a white amorphous solid: ¹ H NMR (300 MHz,CDCl₃) δ (TMS) 7.81 (s, 1H, triazole), 7.78 (s, 1H, triazole), 7.66 (dt,J_(t) =2, J_(d) =8.4, 2H, arom), 7.43 (dt, J_(t) =2, J_(d) =8.4, 2H,arom), 7.36 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.98 (s, 1H, furan),6.8-6.6 (m, 2H, arom), 6.60 (br d, J=9.3, 1H, NH), 5.34 (s, 1H, OH),5.03 (d, J=14.2, 1H, TrCH(H)), 4.93 (br quint, J=7, 1H, CHMe), 4.50 (d,J=14.2, 1H, TrCH(H)), 1.00 (d, J=6.8, 3H, MeCH); GC/MS 316 and 318(ethylaminoacyl group, C₁₄ H₁₀ ClF₃ NO₂), 273 and 275 (acyl group, C₁₂H₅ ClF₃ O₂), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-84.6° (c 1,CHCl₃). Analysis calculated for C₂₄ H₁₈ ClF₅ N₄ O₃ : C 53.30; H 3.35; N10.36. Found: C 53.12; H 3.82; N 10.36.

EXAMPLE 45 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methyloxazole-5-carboxamide

A solution of N-(4-chlorobenzoyl)-L-alanine (1.46 g, 6.41 mmol) inbenzene (35 mL) was treated with oxalyl chloride (0.55 mL, 6.41 mmol) at45° C. for 3 h. Next, a solution of(2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(1.72 g, 6.41 mmol) and triethylamine (2.2 mL) in CHCl₂ (20 mL) wasslowly added and the reaction mixture was stirred at 0° C. for 0.5 h.The crude product was then poured into cold water and extracted withCHCl₃. The organic solution was dried over Na₂ SO₄, filtered and thefiltrate was concentrated in vacuo to give a mixture of several products(TLC) from which the title compound was isolated by flash chromatographyas a white solid (140 mg): mp 89°-93° C.; ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 8.04 (d, J=8.5, 2H, arom), 7.79 (s, 1H, triazole), 7.78 (s, 1H,triazole), 7.49 (d, J=8.5, 2H, arom), 7.37 (dt, J_(d) =6.5, J_(t) =8.8,1H, arom), 6.8-6.6 (m, 3H, arom, NH), 5.38 (d, J=1.1, 1H, OH), 5.04 (d,J=14.3, 1H, TrCH(H)), 4.96 (br quint, J=7, 1H, CHMe), 4.53 (d, J=14.3,1H, TrCH(H)), 2.60 (s, 3H, Me-oxazole), 1.04 (d, J=6.8, 3H, MeCH);HPLC-MS 263 and 265 (ethylaminoacyl group, C₁₃ H₁₂ ClN₂ O₂), 220 and 222(acyl group, C₁₁ H₇ ClNO₂), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D)=-141° (c 0.5, CHCl₃). Analysis calculated for C₂₃ H₂₀ ClF₂ N₅ O₃ : C56.62; H 4.13; N 14.35. Found: C 56.41; H 4.19; N 14.50.

EXAMPLE 46 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-thiazole-4-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-chlorophenyl)thiazole-4-carboxylic acid (reference example 31) thetitle compound was obtained as a white solid: mp 201°-204° C.; ¹ H NMR(80 MHz, CDCl₃) δ (TMS) 8.15 (s, 1H, thiazole), 8.0-7.7 (m, 4H,triazole, arom), 7.6-7.2 (3H, arom), 7.0-6.6 (m, 2H, arom), 5.33 (d,J=1.3, 1H, OH), 5.06 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe),4.5 (d, J=14.5, 1H, TrCH(H)), 1.07 (d, J=7, 3H, MeCH); α!^(D) =-130.7°(c 1, CHCl₃). Analysis calculated for C₂₂ H₁₈ ClF₂ N₅ O₂ S: C 53.94; H3.70; N 14.29; S 6.54. Found: C 54.03; H 4.05; N 13.85; S 6.51.

EXAMPLE 47 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(-1,2,4-triazol-1-yl)propyl!-2-(4-trifluoromethylphenyl)thiazole-4-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-trifluoromethylphenyl)thiazole-4-carboxylic acid (reference example32) the title compound was obtained as a white solid: mp 167°-168° C.; ¹H NMR (80 MHz, CDCl₃) δ (TMS) 8.21 (s), 8.16 (s), 8.07 (s), 8.1-7.6 (m,arom), 7.6-7.3 (1H, arom), 7.0-6.6 (m, 2H, arom), 5.34 (d, J=1.3, 1H,OH), 5.06 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.5 (d,J=14.5, 1H, TrCH(H)), 1.08 (d, J=7, 3H, MeCH); α!^(D) =-136.7° (c 1,CHCl₃). Analysis calculated for C₂₃ H₁₈ F₅ N₅ O₂ S: C 52.77; H 3.47; N13.38; S 6.12. Found: C 52.92; H 3.47; N 13.42; S 6.08.

EXAMPLE 48 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-phenylthiazole-4-carboxamide

Following a similar procedure to that described in example 1 but using2-phenylthiazole-4-carboxylic acid (reference example 33) the titlecompound was obtained as a white solid: mp 174°-175° C;. ¹ H NMR (80MHz, CDCl₃) δ (TMS) 8.15 (s), 8.1-7.9 (m, arom), 7.81 (s), 7.75 (s),7.6-7.3 (m, 4H, arom), 7.0-6.6 (m, 2H, arom), 5.35 (d, J=1.3, 1H, OH),5.06 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.5 (d, J=14.5,1H, TrCH(H)), 1.08 (d, J=7, 3H, MeCH); α!^(D) =-145.5° (c 1, CHCl₃).Analysis calculated for C₂₂ H₁₉ F₂ N₅ O₂ S: C 58.01; H 4.20; N 15.38; S7.04. Found: C 58.11; H 4.59; N 15.34; S 6.85.

EXAMPLE 49 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-4-(2,2,3,3-tetrafluoropropoxy)phenyl!thiazole-4-carboxamide

Following a similar procedure to that described in example 1 but using2- 4-(2,2,3,3-tetrafluoropropoxy)phenyl!thiazole-4-carboxylic acid(reference example 34) the title compound was obtained as an amorphoussolid: ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.10 (s), 8.1-7.8 (m, arom),7.6-7.4 (m, 1H, arom), 7.2-6.7 (m, 2+1/4H, arom, CHF₂), 6.07 (t, J=4.3,1/2H, CHF₂), 5.41 (t, J=4.3, 1/4H, CHF₂), 5.34 (d, J=1.3, 1H, OH), 5.06(d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.5 (d, J=14.5, 1H,TrCH(H)), 4.44 (tt, J=0.8, J=12, 2H, OCH₂),1.07 (d, J=7, 3H, MeCH);α!^(D) =-123.8° (c 1, CHCl₃). Analysis calculated for C₂₅ H₂₁ F₆ N₅ O₃S: C 51.28; H 3.62; N 11.96; S 5.48. Found: C 50.89; H 3.90; N 11.34; S5.34.

EXAMPLE 50 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-(3-pyridyl)thiazole-4-carboxamide

Following a similar procedure to that described in example 1 but using2-(3-pyridyl)thiazole-4-carboxylic acid the title compound was obtainedas a white solid: mp 182°-183° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 9.23(br s, 1H, pyridine), 8.7 (br s, 1H, pyridine), 8.34 (br s, 1/2H,pyridine), 8.21 (s, 1.5H, thiazole, pyridine), 8.1-7.7 (m, triazole),7.6-7.3 (m, 2H, arom, pyridine), 7.0-6.6 (m, 2H, arom), 5.34 (d, J=1.3,1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d,J=14.5, 1H, TrCH(H)), 1.08 (d, J=7, 3H, MeCH); α!^(D) =-151.30 (c 1,CHCl₃). Analysis calculated for C₂₁ H₁₈ F₂ N₆ O₂ S: C 55.26; H 3.97; N18.41; S 7.02 Found: C 55.14; H 3.93; N 18.41; S 6.81.

EXAMPLE 51 (1R,2R)-5-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!thiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)thiophene-2-carboxylic acid (prepared as described inHauptmann et al, Tetrahedron Lett. 1968, 1317) the title compound wasobtained as a white solid: mp 169°-170° C.; ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 7.79 (s, 1H, triazole), 7.78 (s, 1H, triazole), 7.55 (dt, J_(t)=2.5, J_(d) =6.6, 2H, arom), 7.54 (d, J=3.5, 1H, thiophene), 7.38 (dt,J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.38 (dt, J_(t) =2.5, J_(d) =6.6, 2H,arom), 7.25 (d, J=3.5, 1H, thiophene), 6.8-6.6 (m, 2H, arom), 6.53 (brd, J=9.5, 1H, NH), 5.35 (d, J=1.5, 1H, OH), 5.04 (d, J=14.3, 1H,TrCH(H)), 4.93 (br quint, J=7, 1H, CHMe), 4.51 (d, J=14.3, 1H, TrCH(H)),1.02 (d, J=6.8, 3H MECH); MS 264 and 266 (ethylaminoacyl group, C₁₃ H₁₁ClNOS), 221 and 223 (acyl group, C₁₁ H₆ ClOS), 224 (Tr--CH₂ COHAr, ClOH₈F₂ N₃ O); α!^(D) =-401.0° (c 1, CHCl₃). Analysis calculated for C₂₃ H₁₉ClF₂ N₄ O₂ S: C 56.50 H 3.92; N 11.46; S 6.56. Found: C 56.52; H 3.93; N11.39; S 6.11.

EXAMPLE 52 (1R,2R)-5(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!thiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-cyanophenyl)thiophene-2-carboxylic acid (reference example 35) thetitle compound was obtained as a white solid: mp 210°-211° C.; ¹ H NMR(300 MHz, CDCl₃) δ (TMS) 7.80 (s, 1H, triazole), 7.79 (s, 1H, triazole),7.71 (d, J=8, 2H, arom), 7.70 (d, J=8, 2H, arom), 7.58 (d, J=3.9, 1H,thiophene), 7.41 (d, J=3.9, 1H, thiophene), 7.39 (dt, J_(d) =6.5, J_(t)=8.8, 1H, arom), 6.8-6.6 (m, 2H, arom), 6.57 (br d, J=9.4, 1H, NH), 5.37(d, J=1.5, 1H, OH), 5.05 (d, J=14.3, 1H, TrCH(H)), 4.94 (br quint, J=7,1H, CHMe), 4.52 (d, J=14.3, 1H, TrCH(H)), 1.03 (d, J=6.8, 3H, MeCH);HPLC-MS 212 (acyl group, C₁₂ H₆ NOS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃O); α!^(D) =-105.6° (c 1, CHCl₃). Analysis calculated for C₂₄ H₁₉ F₂ N₅O₂ S: C 60.12 H 3.99; N 14.61; S 6.69. Found: C 58.98; H 3.90; N 14.26;S 6.28.

EXAMPLE 53 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-(2-pyridyl)thiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using5-(2-pyridyl)thiophene-2-carboxylic acid the title compound was obtainedas a white solid: mp 212°-213° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.60(dt, J_(t) =1, 1J_(t) =5, 1H, arom), 7.9-7.5 (m, arom), 7.5-7.2 (m,arom), 6.9-6.5 (m, arom, NH), 5.34 (d, J=1.3, 1H, OH), 5.05 (d, J=14.5,1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 1.02(d, J=7, 3H, MeCH); α!^(D) =-116.8° (c 1, CHCl₃). Analysis calculatedfor C₂₂ H₁₉ F₂ N₅ O₂ S: C 58.01; H 4.20; N 15.38; S 7.04. Found: C58.20; H 4.55; N 15.82; S 6.85.

EXAMPLE 54 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl!thiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using5- 1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl!thiophene-2-carboxylicacid the title compound was obtained as a white solid: mp 106°-110° C; ¹H NMR (300 MHz, CDCl₃) δ (TMS) 7.79 (s, 1H, triazole), 7.77 (s, 1H,triazole), 7.54 (d, J=3.8, 1H, thiophene), 7.38 (dt, J_(d) =6.5, J_(t)=8.8, 1H, arom), 7.30 (d, J=3.8, 1H, thiophene), 6.84 (s, 1H, pyrazole),6.8-6.6 (m, 2H, arom), 6.52 (br d, J=9.3, 1H, NH), 5.34 (d, J=1.5, 1H,OH), 5.03 (d, J=14.3, 1H, TrCH(H)), 4.93 (br quint, J=7, 1H, CHMe), 4.52(d, J=14.3, 1H, TrCH(H)), 4.03 (s, 3H, Me-pyrazole), 1.01 (d, J=6.8, 3H,MeCH); MS 302 (ethylaminoacyl group, C₁₂ H₁₁ F₃ N₃ OS), 259 (acyl group,C₁₀ H₆ F₃ N₂ O₅), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-90.1° (c1, CHCl₃). Analysis calculated for C₂₂ H₁₉ F₅ N₆ O₂ S: C 50.19; H 3.64;N 15.96; S 6.09. Found: C 50.27; H 3.77; N 15.71; S 5.58.

EXAMPLE 55 (1R,2R)-5-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-3-methylthiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)-3-methylthiophene-2-carboxylic acid (referenceexample 36) the title compound was obtained as an amorphous solid: ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 7.84 (s, 1H, triazole), 7.82 (s, 1H,triazole), 7.56 (dt, J_(t) =2.5, J_(d) =6.6, 2H, arom), 7.40 (dt, J_(d)=6.5, J_(t) =8.8, 1H, arom), 7.39 (d, J=7, 2H, arom), 7.14 (s, 1H,thiophene), 6.8-6.6 (m, 2H, arom), 6.42 (br d, J=9.3, 1H, NH), 5.38 (brs, 1H, OH), 5.08 (d, J=14.5, 1H, TrCH(H)), 4.95 (br quint, J=7, 1H,CHMe), 4.55 (d, J=14.5, 1H, TrCH(H)), 2.82 (s, 3H, Me-thiophene), 1.04(d, J=6.8, 3H, MeCH); MS 278 and 280 (ethylaminoacyl group, C₁₄ H₁₃ClNOS), 235 and 237 (acyl group, C₁₂ H₈ ClOS), 224 (Tr--CH₂ COHAr, C₁₀H₈ F₂ N₃ O); α!^(D) =-114.9° (c 1, CHCl₃). Analysis calculated for C₂₄H₂₁ ClF₂ N₄ O₂ S: C 57.31 H 4.21; N 11.14; S 6.37. Found: C 57.39; H4.21; N 11.21; S 6.59.

EXAMPLE 56 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-3-methyl-5-(4-trifluoromethylphenyl)thiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using3-methyl-5-(4-trifluoromethylphenyl)thiophene-2-carboxylic acid(obtained by a similar procedure to that described in reference example36) the title compound was obtained as an amorphous solid: MS 312(ethylaminoacyl group, C₁₅ H₁₃ F₃ NOS), 269 (acyl group, C₁₃ H₉ F₃ OS),224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-104.20 (c 1, CHCl₃).Analysis calculated for C₂₅ H₂₁ F₅ N₄ O₂ S: C 55.97 H 3.95; N 10.44; S5.98. Found: C 56.27; H 4.00; N 10.58; S 5.77.

EXAMPLE 57 (1R,2R)-5-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-3-methylthiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-cyanophenyl)-3-methylthiophene-2-carboxylic acid (reference example37) the title compound was obtained as a white solid: mp 176°-177° C.; ¹H NMR (300 MHz, CDCl₃) δ (TMS) 7.79 (s, 1H, triazole), 7.78 (s, 1H,triazole), 7.69 (s, 4H, arom), 7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H,arom), 7.23 (s, 1H, thiophene), 6.9-6.6 (m, 2H, arom), 6.43 (br d,J=9.4, 1H, NH), 5.35 (d, J=1.3, 1H, OH), 5.04 (d, J=14.2, 1H, TrCH(H)),4.93 (br quint, J=7, 1H, CHMe), 4.52 (d, J=14.2, 1H, TrCH(H)), 2.60 (s,3H, Me-thiophene), 1.02 (d, J=6.8, 3H, MeCH); GC/MS 269 (ethylaminoacylgroup, C₁₅ H₁₃ N₂ OS), 226 (acyl group, C₁₃ H₈ NOS), 224 (Tr--CH₂ COHAr,C₁₀ H₈ F₂ N₃ O); α!^(D) =-116.3° (c 1, CHCl₃). Analysis calculated forC₂₅ H₂₁ F₂ N₅ O₂ S: C 60.84 H 4.29; N 14.19; S 6.50. Found: C 60.54; H4.25; N 13.81; S 5.90.

EXAMPLE 58 (1R,2R)-3-Amino-5-(4-chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!thiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using3-amino-5-(4-chlorophenyl)thiophene-2-carboxylic acid (obtained asdescribed in Hartmann, Synthesis 1984, 275) the title compound wasobtained as a yellow solid: mp 107°-111° C.; ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 7.79 (s, 2H, triazole), 7.61 (dt, J_(t) =2, J_(d) =9, 2H, arom),7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.37 (dt, J_(t) =2, J_(d)=9, 2H, arom), 6.9-6.6 (m, 2H, arom), 6.78 (s, 1H, thiophene), 5.93 (brd, J=9.3, 1H, NH), 5.69 (br s, 2H, NH₂), 5.35 (d, J=1.3, 1H, OH), 5.02(d, J=14.3, 1H, TrCH(H)), 4.88 (br quint, J=7, 1H, CHMe), 4.52 (d,J=14.3, 1H, TrCH(H)), 1.01 (d, J=6.8, 3H, MeCH); HPLC-MS 279 and 281(ethylaminoacyl group, C₁₃ H₁₂ ClN₂ OS), 236 (acyl group, C₁₁ H₇ ClNOS);α!^(D) =-137.8° (c 1, CHCl₃). Analysis calculated for C₂₃ H₂₀ ClF₂ N₅ O₂S: C 54.82; H 4.00; N 13.90; S 6.36. 2 5 Found: C 55.42; H 4.19; N13.34; S 5.35.

EXAMPLE 59 (1R,2R)-3-Amino-4- (4-chlorophenyl)sulfonyl!-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!thiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using3-amino-4- (4-chlorophenyl)sulfonyl!thiophene-2-carboxylic acid thetitle compound was obtained as a hygroscopic amorphous solid: ¹ H NMR(80 MHz, CDCl₃) δ (TMS) 8.1-7.7 (m, arom), 7.9-7.5 (m, arom), 7.6-7.3(m, arom), 6.9-6.5 (m, arom, NH₂), 6.00 (br d, J=9.5, 1H, NH), 5.31 (d,J=1.5, 1H, OH), 4.95 (d, J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe),4.44 (d, J=14.5, 1H, TrCH(H)), 0.96 (d, J=7, 3H, MeCH); α!^(D) =-59.20(c 1, CHCl₃). Analysis calculated for C₂₃ H₂₀ ClF₂ N₅ O₄ S₂ : C 48.64 H3.55; N 12.33; S 11.29. Found: C 48.27; H 3.91; N 12.60; S 10.65.

EXAMPLE 60 (1R,2R)-4- (4-Chlorophenyl)sulfonyl!-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-3-methylthiophene-2-carboxamide

Following a similar procedure to that described in example 1 but using4- (4-chlorophenyl)sulfonyl!-3-methylthiophene-2-carboxylic acid thetitle compound was obtained as a white amorphous solid: ¹ H NMR (80 MHz,CDCl₃) δ (TMS) 8.33 (s, 1H, thiophene), 7.85 (d, J=8.8, 2H, arom), 7.78(s, 1H, triazole), 7.75 (s, 1H, triazole), 7.50 (d, J=8.8, 2H, arom),7.41 (dt, J_(d) =6.5, J_(t) =9, 1H, arom), 6.9-6.6 (m, 2H, arom), 6.42(br d, J=9.5, 1H, NH), 5.32 (d, J=1.5, 1H, OH), 4.99 (d, J=14.5, 1H,TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.41 (d, J=14.5, 1H, TrCH(H)), 2.54 (s,3H, Me-thiophene), 0.98 (d, J=7, 3H, MeCH); α!^(D) =-73.8° (c 1, CHCl₃).Analysis calculated for C₂₄ H₂₁ ClF₂ N₄ O₄ S₂ : C 50.84 H 3.73; N 9.88;S 11.31. Found: C 51.23; H 4.12; N 9.67; S 10.62.

EXAMPLE 61 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-3H-imidazole-4-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-chlorophenyl)-5-methyl-3H-imidazole-4-carboxylic acid (referenceexample 38) the title compound was obtained as a white solid: mp165°-166° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 9.48 (br s, 1H,NH-imidazole), 7.81 (s, 1H, triazole), 7.78 (d, J=8.8, 2H, arom), 7.75(s, 1H, triazole), 7.71 (d, J=9.6, 1H, NH), 7.43 (dt, J_(d) =6.5, J_(t)=8.8, 1H, arom), 7.42 (d, J=8.8, 2H, arom), 6.8-6.6 (m, 2H, arom), 5.38(s, 1H, OH), 5.03 (d, J=14.3, 1H, TrCH(H)), 4.85 (br quint, J=7, 1H,CHMe), 4.60 (d, J=14.3, 1H, TrCH(H)), 2.68 (s, 3H, Me-imidazole), 1.07(d, J=6.8, 3H, MeCH); HPLC-MS 262 and 264 (ethylaminoacyl group, C₁₃ H₁₃ClN₃ O), 219 (acyl group, C₁₁ H₈ ClN₂ O); α!^(D) =-105.9° (c 1, MeOH).Analysis calculated for C₂₃ H₂₁ ClF₂ N₆ O₂ : C 56.74; H 4.35; N 17.26.Found: C 54.48; H 4.05; N 16.09.

EXAMPLE 62 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-3,5-dimethyl-3H-imidazole-4-carboxamide

Following a similar procedure to that described in example 1 but usingthe mixture of acids obtained in reference example 39(2-(4-chlorophenyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid and2-(4-chlorophenyl)-1,5-dimethyl-1H-imidazole-4-carboxylic acid) twoproducts were obtained, which were easily separated by flashchromatography. The less polar product (TLC in EtOAc) was identified byNOE as the title compound and was isolated as a white amorphous solid: ¹H NMR (300 MHz, CDCl₃) δ (TMS) 7.81 (s, 1H, triazole), 7.78 (s, 1H,triazole), 7.55 (d, J=8.5, 2H, arom), 7.45 (d, J=8.5, 2H, arom), 7.40(dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 2H, arom), 6.39 (d,J=9.5, 1, NH), 5.37 (d, J=1.5, 1H, OH), 5.05 (d, J=14.3, 1H, TrCH(H)),4.96 (br quint, J=7, 1H, CHMe), 4.53 (d, J=14.3, 1H, TrCH(H)), 3.87 (s,3H, N-Me), 2.61 (s, 3H, Me-imidazol), 1.03 (d, J=6.8, 3H, MeCH); GC/MS276 and 278 (ethylaminoacyl group, C₁₄ H₁₅ ClN₃ O), 198 and 200 (acylgroup, C₁₂ H₁₀ N₂ O), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D)=-71.4° (c 1, CHCl₃). Analysis calculated for C₂₄ H₂₃ ClF₂ N₆ O₂.H₂ O: C55.55; H 4.86; N 16.19. Found: C 55.11; H 4.75; N 15.93.

EXAMPLE 63 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1,5-dimethyl-1H-imidazole-4-carboxamide

In the flash chromatography of the preceding example a second more polarproduct also eluted, which was identified by NOE as the title compoundand which was also obtained as a white amorphous solid: ¹ H NMR (300MHz, CDCl₃) δ (TMS) 7.81 (s, 1H, triazole), 7.73 (s, 1H, triazole), 7.68(br d, J=9.4, 1H, NH), 7.57 (d, J=8.5, 2H, arom), 7.48 (d, J=8.5, 2H,arom), 7.40 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 2H,arom), 5.36 (d, J=1.5, 1H, OH), 5.03 (d, J=14.3, 1H, TrCH(H)), 4.83 (brquint, J=7, 1H, CHMe), 4.56 (d, J=14.3, 1H, TrCH(H)), 3.59 (s, 3H,N--Me), 2.68 (s, 3H, Me-imidazol), 1.04 (d, J=6.8, 3H, MeCH); GC/MS 276and 278 (ethylaminoacyl group, C₁₄ H₁₅ ClN₃ O), 198 and 200 (acyl group,C₁₂ H₁₀ N₂ O), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-108.7° (c1, CHCl₃). Analysis calculated for C₂₄ H₂₃ ClF₂ N₆ O₂.H₂ O: C 55.55; H4.86; N 16.19. Found: C 55.68; H 4.94; N 15.75.

EXAMPLE 64 (1R,2R)-5-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1,3,4-oxadiazole-2-carboxamide,chloroform solvate

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylic acid (reference example40) and recrystallizing the final product from CHCl₃ the title compoundwas obtained as a white solid: mp 188°-190° C.; ¹ H NMR (300 MHz,MeOH--d₄) δ (MeOH--d₄) 8.24 (s, 1H, triazole), 7.9-7.8 (m, 2H, arom),7.68 (s, 1H, triazole), 7.52 (dt, J_(t) =2, J_(d) =8.7, 2H, arom), 7.35(dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 6.95 (ddd, J=2.4, J=8.7, J=11.5,1H, arom), 6.81 (dt, J_(d) =2.0, J_(t) =8.0, 1H, arom), 4.88 (d, J=14.4,1H, TrCH(H)), 4.82 (m, 1H, CHMe), 4.54 (d, J=14.4, 1H, TrCH(H)), 0.99(d, J=6.8, 3H, MeCH); HPLC-MS 250 and 252 (ethylaminoacyl group, C₁₁ H₉ClN₃ O₂), 207 and 209 (acyl group, C₉ H₄ ClN₂ O₂), 224 (Tr--CH₂ COHAr,C₁₀ H₈ F₂ N₃ O); α!^(D) =-66.5° (c 1, MeOH).

EXAMPLE 65 (1R,2R)-3-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1,2,4-oxadiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using3-(4-chlorophenyl)-1,2,4-oxadiazole-5-carboxylic acid (reference example41) the title compound was obtained as a white solid: mp 170°-172° C.; ¹H NMR (300 MHz, CDCl₃) δ (TMS) 8.10 (dt, J_(t) =2, J_(d) =9, 2H, arom),7.81 (s, 1H, triazole), 7.79 (s, 1H, triazole), 7.69 (br d, J=9.3, 1H,NH), 7.52 (dt, J_(t) =2, J_(d) =9, 2H, arom), 7.40 (dt, J_(d) =6.5,J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 2H, arom), 5.46 (d, J=1.5, 1H, OH),5.02 (d, J=14.2, 1H, TrCH(H)), 4.95 (br quint, J=7, 1H, CHMe), 4.52 (d,J=14.2, 1H, TrCH(H)), 1.07 (d, J=6.8, 3H, MeCH); HPLC-MS 250 and 252(ethylaminoacyl group, C₁₁ H₉ ClN₃ O₂), 207 and 209 (acyl group, C₉ H₄ClN₂ O₂), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-81.8° (c 1,MeOH).

EXAMPLE 66 (1R,2R)-5(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1,2,4-oxadiazole-3-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)-1,2,4-oxadiazole-3-carboxylic acid (reference example42) the title compound was obtained as a white solid: mp 79°-83° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 8.16 (dt, J_(t) =1.8, J_(d) =8.6, 2H,arom), 7.79 (br s, 2H, triazole), 7.60 (br d, J=9.3, 1H, NH), 7.56 (dt,J_(t) =1.8, J_(d) =8.6, 2H, arom), 7.40 (dt, J_(d) =6.5, J_(t) =8.8, 1H,arom), 6.8-6.6 (m, 2H, arom), 5.38 (d, J=1.5, 1H, OH), 5.04 (d, J=14.4,1H, TrCH(H)), 4.95 (br quint, J=7, 1H, CHMe), 4.53 (d, J=14.4, 1H,TrCH(H)), 1.06 (d, J=6.8, 3H, MeCH); HPLC-MS 250 and 252 (ethylaminoacylgroup, C₁₁ H₉ ClN₃ O₂), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D)=-67.4° (c 1, MeOH).

EXAMPLE 67 (1R,2R)-3-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1,2,4-thiadiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using3-(4-chlorophenyl)-1,2,4-thiadiazole-5-carboxylic acid (prepared asdescribed in Howe et al, J. Org.Chem. 1977, 42, 1813) the title compoundwas obtained as a white solid: mp 215°-220° C.; ¹ H NMR (300 MHz,MeOH--d₄) δ (MeOH--d₄) 8.45 (dt, J_(t) =2, J_(d) =7, 2H, arom), 8.32 (s,1H, triazole), 7.75 (s, 1H, triazole), 7.65 (dt, J_(t) =2, J_(d) =7, 2H,arom), 7.50 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.08 (ddd, J=2.4,J=8.7, J=11.5, 1H, arom), 6.94 (dt, J_(d) =2.0, J_(t) =8.0, 1H, arom),5.12 (q, J=6.8, 1H, CHMe), 5.05 (d, J=14.6, 1H, TrCH(H)), 4.70 (d,J=14.6, 1H, TrCH(H)), 1.18 (d, J=6.8, 3H, MeCH); HPLC-MS 266 and 268(ethylaminoacyl group, C₁₁ H₉ ClN₃ OS), 223 and 225 (acyl group, C₉ H₄ClN₂ OS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-106.3° (c 1,HCl₃).

EXAMPLE 68 (1R,2R)-5-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-1,2,4-thiadiazole-3-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)-1,2,4-thiadiazole-3-carboxylic acid (prepared asdescribed in Howe et al, J.Org.Chem. 1977, 42, 1813) the title compoundwas obtained as a white solid: mp 186°-187° C.; ¹ H NMR (300 MHz,MeOH--d₄) δ (MeOH) 8.32 (s, 1H, triazole), 8.22 (dt, J_(t) =2, J_(d)=8.4, 2H, arom), 7.76 (s, 1H, triazole), 7.70 (dt, J_(t) =2, J_(d) =8.4,2H, arom), 7.49 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.08 (ddd,J=2.4, J=8.7, J=11.5, 1H, arom), 6.94 (dt, J_(d) =2.0, J_(t) =8.0, 1H,arom), 5.15 (q, J=6.8, 1H, CHMe), 5.05 (d, J=14.6, 1H, TrCH(H)), 4.70(d, J=14.6, 1H, TrCH(H)), 1.17 (d, J=6.8, 3H, MeCH); HPLC-MS 266 and 268(ethylaminoacyl group, C₁₁ H₉ ClN₃ OS), 223 and 225 (acyl group, C₉ H₄ClN₂ OS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-80.80 (c 1,CHCl₃).

EXAMPLE 69 (1R,2R)-3-(2-Chloro-6-fluorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methylisoxazole-4-carboxamide

Following a similar procedure to that described in example 1 but using3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid thetitle compound was obtained as an amorphous solid: ¹ H NMR (80 MHz,CDCl₃) δ (TMS) 7.77 (s, 1H, triazole), 7.70 (s, 1H, triazole), 7.6-7.0(m, 4H, arom), 6.9-6.5 (m, 2H, arom), 5.88 (br d, J=9, 1H, NH), 4.83 (d,J=14.5, 1H, TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.17 (d, J=14.5, 1H,TrCH(H)), 2.83 (s, 3H, Me-isoxazole), 0.74 (d, J=6.6, 3H, MeCH); α!^(D)=-98.2° (c 1, CHCl₃). Analysis calculated for C₂₃ H₁₉ ClF₃ N₅ O₃ : C54.61; H 3.79; N 13.84. Found: C 55.38; H 4.02; N 13.76.

EXAMPLE 70 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!4-(1,2,3-thiadiazol-4-yl)benzamide

Following a similar procedure to that described in example 1 but using4-(1,2,3-thiadiazol-4-yl)benzoic acid the title compound was obtained asa yellow solid: mp 196°-198° C.; ¹ H NMR (80 MHz, CDCl₃) δ (TMS) 8.76(s, 1H, thiadiazole), 8.29 (d, J=8, 2H, arom), 7.98 (d, J=8, 2H, arom),7.40 (dt, J_(d) =6.5, J_(t) =8.5, 1H, arom), 7.79 (s, 2H, triazole),6.9-6.5 (m, 3H, arom, NH), 5.37 (br s, 1H, OH), 5.08 (d, J=14.5, 1H,TrCH(H)), 5.1-4.8 (m, 1H, CHMe), 4.50 (d, J=14.5, 1H, TrCH(H)), 1.06 (d,J=7, 3H, MeCH); α!^(D) =-121.2° (c 1, CHCl₃). Analysis calculated forC₂₁ H₁₈ F₂ N₆ O₂ S: C 55.26; H 3.97; N 18.41; S 7.02. Found: C 55.65; H4.11; N 19.05; S 7.39.

EXAMPLE 71 (1R,2R)-5-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!nicotinamide

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)nicotinic acid the title compound was obtained: mp93°-101° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 9.02 (d, J=2.1, 1H, pyr),8.96 (d, J=2.2, 1H, pyr), 8.33 (t, J=2.2, 1H, pyr), 7.8 (s, 1H,triazole), 7.79 (s, 1H, triazole), 7.58 (dt, J_(t) =2, J_(d) =8.7, 2H,arom), 7.49 (dt, J_(t) =2, J_(d) =8.7, 2H, arom), 7.39 (dt, J_(d) =6.5,J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 3H, arom, NH), 5.41 (d, J=1.4, 1H,OH), 5.06 (d, J=14.2, 1H, TrCH(H)), 5.03 (br quint, J=7, 1H, CHMe), 4.50(d, J=14.2, 1H, TrCH(H)), 1.06 (d, J=6.8, 3H, MeCH); GC/MS 259 and 261(ethylaminoacyl group, C₁₄ H₁₂ ClN₂ O), 216 and 218 (acyl group, C₁₂ H₇ClNO), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-96.6° (c 1, CHCl₃).

EXAMPLE 72 (1R,2R)-3-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!benzamide

Following a similar procedure to that described in example 1 but using3-(4-chlorophenyl)benzoic acid the title compound was obtained as awhite solid: mp 90°-91° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.05 (t,J=1.7, 1H, arom), 7.80 (dt, J_(t) =1.2, J_(d) =8.3, 1H, arom), 7.79 (s,2H, triazole), 7.72 (dt, J_(t) =1.2, J_(d) =8.3, 1H, arom), 7.56 (dt,J_(t) =2, J_(d) =8.7, 2H, arom), 7.5-7.6 (m, 1H, arom), 7.44 (dt, J_(t)=2, J_(d) =8.7, 2H, arom), 7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom),6.8-6.6 (m, 3H, arom, NH), 5.36 (d, J=1.2, 1H, OH), 5.08 (d, J=14.2, 1H,TrCH(H)), 5.01 (br quint, J=7, 1H, CHMe), 4.50 (d, J=14.2, 1H, TrCH(H)),1.05 (d, J=6.8, 3H, MeCH); CC/MS 258 and 260 (ethylaminoacyl group, C₁₅H₁₃ ClNO), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O), 215 and 217 (acyl group,C₁₃ H₈ ClO); α!^(D) =-97.7° (c 1, CHCl₃).

EXAMPLE 73 (1R,2R)-4-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!benzamide

Following a similar procedure to that described in example 1 but using4-(4-chlorophenyl)benzoic acid the title compound was obtained as awhite solid: mp 173°-174° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.93 (dt,J_(t) =1.7, J_(d) =8.4, 2H, arom), 7.79 (s, 2H, triazole), 7.66 (dt,J_(t) =1.7, J_(d) =8.4, 2H, arom), 7.55 (dt, J_(t) =2, J_(d) =8.6, 2H,arom), 7.44 (dt, J_(t) =2, J_(d) =8.6, 2H, arom), 7.40 (dt, J_(d) =6.5,J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 3H, arom, NH), 5.37 (br s, 1H, OH),5.08 (d, J=14.3, 1H, TrCH(H)), 5.00 (br quint, J=7, 1H, CHMe), 4.50 (d,J=14.3, 1H, TrCH(H)), 1.04 (d, J=6.8, 3H, MeCH); GC/MS 258 and 260(ethylaminoacyl group, C₁₅ H₁₃ ClNO), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃O), 215 and 217 (acyl group, C₁₃ H₈ ClO); α!^(D) =-110.2° (c 1, CHCl₃).

EXAMPLE 74 (1R,2R)-2-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-7-methylpyrazolo,1,5-a!pyrimidine-6-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-chlorophenyl)-7-methylpyrazolo 1,5-a!pyrimidine-6-carboxylic acidthe title compound was obtained as a white solid: mp 227°-228 ° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 8.61 (s, 1H, arom), 7.99 (dt, J_(t) =2.0,J_(d) =8.6, 2H, arom), 7.83 (s, 2H, triazole), 7.47 (dt, J_(t) =2.0,J_(d) =8.6, 2H, arom), 7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.03(s, 1H, arom), 6.8-6.6 (m, 2H, arom), 6.62 (br d, J=9.4, 1H, NH), 5.42(s, 1H, OH), 5.13 (d, J=14.2, 1H, TrCH(H)), 5.02 (br quint, J=7, 1H,CHMe), 4.55 (d, J=14.2, 1H, TrCH(H)), 3.13 (s, 3H, Me-heterocycle), 1.09(d, J=6.8, 3H, MeCH); MS 313 and 315 (ethylaminoacyl group, C₁₆ H₁₄ ClN₄O), 270 and 272 (acyl group, C₁₄ H₉ ClN₃ O), 224 (Tr--CH₂ COHAr, C₁₀ H₈F₂ N₃ O); α!^(D) =-93.8° (c 1, CHCl₃). Analysis calculated for C₂₆ H₂₂ClF₂ N₇ O₂ S: C 58.05 H 4.12; N 18.23. Found: C 1 5 58.37; H 4.19; N18.04.

EXAMPLE 75 (1R,2R)-5-(4-Chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!furan-2-carboxamide

Following a similar procedure to that described in example 1 but using5-(4-chlorophenyl)furan-2-carboxylic acid the title compound wasobtained as a white solid: mp 218°-219° C.; ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 7.79 (s, 1H, triazole), 7.78 (s, 1H, triazole), 7.69 (dt, J_(t)=2, J_(d) =8.4, 2H, arom), 7.42 (dt, J_(t) =2, J_(d) =8.4, 2H, arom),7.39 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.25 (d, J=3.6, 1H, furan),6.88 (br d, J=9.5, 1H, NH), 6.8-6.6 (m, 2H, arom), 6.76 (d, J=3.6, 1H,furan), 5.39 (br s, 1H, OH), 5.04 (d, J=14.2, 1H, TrCH(H)), 4.96 (brquint, J=7, 1H, CHMe), 4.53 (d, J=14.2, 1H, TrCH(H)), 1.05 (d, J=6.8,3H, MeCH); GC--MS 248 and 250 (ethylaminoacyl group, C₁₃ H₁₁ ClNO₂), 224(Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O), 205 and 207 (acyl group, C₁₁ H₆ ClO₂);α!^(D) =-173° (c 1, CHCl₃). Analysis calculated for C₂₃ H₁₉ ClF₂ N₄ O₃ :C 58.42; H 4.05; N 11.85. Found: C 57.15; H 3.85; N 10.74.

EXAMPLE 76 (1R*,2R*)-2-(4-Cyanophenyl)-N-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)-2-(4-trifluoromethylphenyl)propyl!-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 29 but using(2R*,3R*)-3-amino-1-(1H-1,2,4-triazol-1-yl)-2-(4-trifluoromethylphenyl)-2-butanol(obtained as described in EP 617031) the title compound was obtained asa white solid: mp 105°-111° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.08(d, J=8.2, 2H, arom), 7.84 (s, 1H, triazole), 7.76 (d, J=8.2, 2H, arom),7.64 (s, 1H, triazole), 7.57 (d, J=8.4, 2H, arom), 7.47 (d, J=8.4, 2H,arom), 6.45 (br d, J=9.2, 1H, NH), 5.46 (d, J=1.0, 1H, OH), 4.75 (d,J=14.2, 1H, TrCH(H)), 4.74 (br quint, J=7, 1H, CHMe), 4.55 (d, J=14.2,1H, TrCH(H)),2.83 (s, 3H, Me-thiazole), 1.03 (d, J=6.8, 3H, MeCH);GC--MS 270 (ethylaminoacyl group, C₁₄ H₁₂ N₃ OS), 256 (Tr--CH₂ COHAr,C₁₁ H₉ F₃ N₃ O), 227 (acyl group, C₁₂ H₇ N₂ OS).

EXAMPLE 77 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-N-methyl-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 29 but using(2R,3R)-3-(N-methylamino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(obtained as described in EP 332,387) the title compound was obtained asa white amorphous solid: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.04 (d,J=8.4, 2H, arom), 7.9-7.7 (m, 4H, triazole, arom), 7.5-7.3 (m, 1H,arom), 6.9-6.7 (m, 2H, arom), 5.5-5.3 (m, 3H, OH, TrCH(H), CHMe), 4.37(d, J=14.2, 1H, TrCH(H)), 3.28 (s, 3H, NMe), 2.55 (s, 3H, Me-thiazole),1.2-1.1 (m, 3H, MeCH); GC--MS 284 (ethylmethylaminoacyl group, C₁₅ H₁₄N₃ OS), 227 (acyl group, C₁₂ H₇ N₂ OS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃O); α!^(D) =-115.2° (c 1, CHCl₃). Analysis calculated for C₂₅ H₂₂ F₂ N₆O₂ S: C 59.05; H 4.36; N 16.53; S 6.30. Found: C 58.81; H 4.53; N 16.42;S 5.69.

EXAMPLE 78 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-N-(2-benzyloxyethyl)-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 29 but using(2R,3R)-3- 2-(benzyloxy)ethyl!amino!-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (obtained as described in EP 617031) thetitle compound was obtained as a white amorphous solid: ¹ H NMR (300MHz, CDCl₃) δ (TMS) 8.1-7.9 (m, arom), 7.76 (s), 7.74 (s), 7.7-7.5 (m,arom), 7.4-7.2 (m, arom), 6.9-6.7 (m, 2H, arom), 5.5 (br m, 1H), 5.04(d, J=14.2, 1H, TrCH(H)), 4.7-4.5 (m, 4H, CH₂ OCH₂), 4.40 (d, J=14.2,1H, TrCH(H)), 4.0-3.5 (m), 2.47 (s, 3H, Me-thiazole), 1.2-1.0 (m, 3H,MeCH); MS (DIP) 284 (ethylbenzyloxyethylaminoacyl, C₂₃ H₂₂ N₃ O₂ S), 227(acyl group, C₁₂ H₇ N₂ OS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D)=-69.7° (c 1, CHCl₃).

EXAMPLE 79 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)-propyl!-N-(ethoxycarbonylmethyl)-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 29 but using(2 R,3)-3-(ethoxycarbonylmethyl)amino!-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(obtained as described in EP 617031) the title compound was obtained asa white amorphous solid: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.08 (m, 2H,arom), 7.8 (m, 4H, triazole, arom), 7.4-7.1 (m, 1H, arom), 6.9-6.7 (m,2H, arom), 5.5 (m, 1H, OH), 5.2-5.1 (m, 2H, CH₂ CO₂ Et), 5.0-4.1 (m, 5H,TrCH₂, CHMe, CH₃ CH₂ O), 2.61 and 2.53 (br s, 3H, Me-thiazole), 1.2-1.0(m, 6H, MeCH, CH₃ CH₂ O); α!^(D) =-142.5° (c 1, CHCl₃). Analysiscalculated for C₂₈ H₂₆ F₂ N₆ O₄ S.1H₂ O: C 56.18; H 4.71; N 14.04; S5.36. Found: C 56.19; H 4.50; N 14.00; S 5.17.

EXAMPLE 80 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-N-(benzyloxycarbonylmethyl)-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 29 but using(2R,3R)-3-(benzyloxycarbonylmethyl)amino!-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(obtained as described in EP 617031) the title compound was obtained asa white amorphous solid: ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.0 (m, 2H,arom), 7.8-7.7 (m, 4H, triazole, arom), 7.4-7.1 (m, 6H, arom), 6.8-6.6(m, 2H, arom), 5.5 (m, 1H, OH), 5.4-4.4 (m, 7H, CH₂ Ph, CH₂ CO₂ Bn,TrCH₂, CHMe), 2.5 (br s, 3H, Me-thiazole), 1.2-1.0 (m, 3H, MeCH); α!^(D)=-114.2° (c 0.2, CHCl₃).

EXAMPLE 81 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-N-(carboxymethyl)-4-methylthiazole-5-carboxamide,trihydrate

A mixture of the product obtained in the preceding example (600 mg, 1mmol), 5% Pd/C (25 mg) and ethanol (25 mL) was hydrogenated (1 atm) atroom temperature for 6 h. The resulting crude product was filteredthrough celite and the filtrate was evaporated to dryness to afford thetitle compound as a white solid (450 mg, 88%): mp 153°-159° C.; α!^(D)=-73.80 (c 0.2, MeOH). Analysis calculated for C₂₆ H₂₂ F₂ N₆ O₄ S.3H₂ O:C 51.48; H 4.65; N 13.85; S 5.29. Found: C 51.85; H 4.40; N 13.60; 54.61.

EXAMPLE 82 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-N-(2-hydroxyethyl)-4-methylthiazole-5-carboxamide

To a solution of the product obtained in example 79 (2.46 g, 4.23 mmol)in ethanol (25 mL) was slowly added NaBH₄ in 3 portions (0.48 mg, 12.7mmol). The mixture was stirred at room temperature for 20 h, and thereaction was then quenched by the addition of saturated aqueous NH₄ Clsolution. The resulting mixture was concentrated and the residuepartitioned between water and CHCl₃. The organic phase was separated,dried over anhydrous Na₂ SO₄, filtered and concentrated to a residue.This was purified by flash chromatography to give the title compound asa white solid: mp 113°-119 ° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.27(br s), 8.05 (br m, 2H, arom), 7.75 (br m, 4H, triazole, arom), 7.36 (m,1H, arom), 6.9-6.5 (m, 2H, arom), 5.71 (br s, 1H, OH), 4.9-4.6 (m, 2H,TrCH(H), CHMe), 4.2-3.5 (m, 5H, NCH₂ CH₂, TrCH(H)), 2.54 and 2.46 (s,3H, Me-thiazole), 1.3-1.1 (m, 3H, MeCH); GC--MS 314(ethylhydroxyethylaminoacyl group, C₁₆ H₁₆ N₁₃ O₂ S), 271(ethylaminoacyl group +1, C₁₄ H₁₂ N₃ OS), 227 (acyl group, C₁₂ H₇ N₂OS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O); α!^(D) =-76.5° (c 1, CHCl₃).

EXAMPLE 83 (4R,5R)-4- 5- 5-(2,4-Difluorophenyl)-4-methyl-5-(1H-1,2,4-triazol-1-yl)methyl!-oxazolidine-3-carbonyl!-4-methylthiazol-2-yl!benzonitrile

Following a similar procedure to that described in example 29 but using(4R,5R)-5-(2,4-difluorophenyl)-4-methyl-5- (1H-1,2,4-triazol-1-yl)methyl!oxazolidine (obtained as described in EP 332,387) the titlecompound was obtained as a white solid: mp 200°-201° C.; ¹ H NMR (300MHz, CDCl₃) δ (TMS) 8.08 (d, J=8.1, 2H, arom), 7.77 (d, J=8.1, 2H,arom), 7.77 (s, 1H, triazole), 7.72 (s, 1H, triazole), 7.31 (dt, J_(d)=6.6, J_(t) =8.7, 1H, arom), 7.0-6.8 (m, 2H, arom), 5.43 (br s, 1H,OCH(H)N), 5.31 (d, J=4.5, 1H, OCH(H)N), 5.1-4.9 (br s, 1H, CHMe), 4.58(AB q, Δv=0.059, J=14.7, 2H, TrCH₂), 2.65 (s, 3H, Me-thiazole), 1.04 (d,J=6.6, 3H, MeCH); GC--MS 227 (acyl group, C₁₂ H₇ N₂ OS); α!^(D) =+17.5°(c 1, CHCl₃). Analysis calculated for C₂₅ H₂₀ F₂ N₆ O₂ S: C 59.28; H3.98; N 16.59; S 6.33. Found: C 59.29; H 3.83; N 16.16; S 6.06.

EXAMPLE 84 (2R,3R)-4- 5- 2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyl!morpholine-4-carbonyl!-4-methylthiazol-2-yl!benzonitrile

A cooled (0° C.) solution of (1R,2R)-2-(4-cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-N-(2-hydroxyethyl)-4-methylthiazole-5-carboxamide(0.45 g, 0.83 mmol, obtained in example 82) in THF (10 mL) was treatedwith diethylazadicarboxylate (0.20 mL, 1.25 mmol) and tributylphosphine(0.31 mL, 1.25 mmol) for 20 h at room temperature. The mixture wasevaporated to dryness and the residue was purified by flashchromatography to give the title compound as a white solid: mp 150°-160°C.; 1H NMR (300 MHz, CDCl₃) δ (TMS) 8.06 (d, J=8.4, 2H, arom), 7.76 (s,1H, triazole), 7.76 (d, J=8.4, 2H, arom), 7.30 (s, 1H, triazole),7.4-7.2 (m, 1H, arom), 7-6.7 (m, 2H, arom), 5.53 (br), 5.17 (d, J=15.1,1H, TrCH(H)), 4.7 (br d, 1H), 4.6-4.4 (m, 1H), 4.0 (br d), 3.6 (br s),2.57 (s, 3H, Me-thiazole), 1.13 (d, J=6.8, 3H, MECH); GC--MS 293 (M⁺-acyl, C₁₄ H₁₅ N₄ F₂ O), 227 (acyl group, C₁₂ H₇ N₂ OS); α!^(D) =-80.5°(c 1, CHCl₃).

EXAMPLE 85 (2R,3R)-4- 5- 2-(2,4-Difluorophenyl)-6-hydroxy-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyl!morpholine-4-carbonyl!-4-methylthiazol-2-yl!benzonitrile

To a cooled (-78° C.) solution of DMSO (0.29 mL, 4.17 mmol) in CH₂ Cl₂(10 mL) was added a solution of trifluoroacetic anhydride (0.30 mL, 2.09mmol) in CH₂ Cl₂ (1 mL) dropwise. After ten minutes, a solution of(1R,2R)-2-(4-cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-N-(2-hydroxyethyl)-4-methylthiazole-5-carboxamide(0.9 g, 1.67 mmol, obtained in example 82) in CH₂ Cl₂ (3 mL) was added.The mixture was stirred for 1 h, and then triethylamine (1.1 mL, 8.3mmol) was added. The reaction mixture was allowed to warm up to -40° C.and was stirred at this temperature for 1.5 h and then at -10° C. for 30min. 10% aqueous NaHCO₃ solution was added, the organic phase wasseparated and the aqueous phase was extracted with chloroform. Thecombined organic extracts were washed with water, dried over anhydrousNa₂ SO₄, filtered and concentrated to a crude product. Purification byflash chromatography afforded the title compound as a white solid: mp225°-228° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.06 and 8.05 (d, J=8.4,2H, arom), 7.77 (s, 1H, triazole), 7.76 (d, J=8.4, 2H, arom), 7.35 (dt,J_(d) =6.5, J_(t) =8.8, 1H, arom), 7.30 (s, 1H, triazole), 7.0-6.7 (m,2H, arom), 5.83 (m, 1H, OCHOH), 5.8-3.2 (several broad signals), 2.57and 2.55 (s, 3H, Me-thiazole), 1.14 (d, J=6.8, 3H, MeCH); α!^(D) =-79.8°(c 1, CHCl₃). Analysis calculated for C₂₆ H₂₂ F₂ N₆ O₃ S.1/2H₂ O: C57.24; H 4.21; N 15.40; S 5.86. Found: C 57.49; H 4.03; N 15.08; S 5.69.

EXAMPLE 86 (2R,3R)-4- 5- 2-(2,4-Difluorophenyl)-3-methyl-6-oxo-2-(-1,2,4-triazol-1-yl)methyl!morpholine-4-carbonyl!-4-methylthiazol-2-yl!benzonitrile

From the first fractions of the above chromatography the title compoundwas isolated as a white amorphous solid: GC--MS 227 (acyl group, C₁₂ H₇N₂ OS).

EXAMPLE 87 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-dichlorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 29 but using(2R,3R)-3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (obtained following the generalprocedure described in J. Org. Chem., 1995, 60, 3000-3012) the titlecompound was obtained as a white solid: mp 109°-113° C.; ¹ H NMR (300MHz, CDCl₃) δ (TMS) 8.07 (dt, J_(t) =1. 8, J_(d) =6.9, 2H, arom), 7.83(s, 1H, triazole), 7.81 (s, 1H, triazole), 7.76 (dt, J_(t) =1.8, J_(d)=6.9, 2H, arom), 7.51 (d, J=8.4, 1H, arom), 7.35 (d, J=2.1, 1H, arom),7.12 (dd, J=2.1, 1J=8.7, 1H, arom), 6.50 (br d, J=9.2, 1H, NH), 5.63 (d,J=14.4, 1H, TrCH(H)), 5.51 (br s, 1H, OH), 5.45 (m, 1H, CHMe), 4.45 (d,J=14.4, 1H, TrCH(H)), 2.83 (s, 3H, Me-thiazole), 0.99 (d, J=6.6, 3H,MeCH); GC--MS 270 (ethylaminoacyl group, C₁₄ H₁₂ N₃ OS), 256 and 258(Tr--CH₂ COHAr, C₁₀ H₈ Cl₂ N₃ O), 227 (acyl group, C₁₂ H₇ N₂ OS); α!^(D)=-106.3° (c 1, CHCl₃). Analysis calculated for C₂₄ H₂₀ Cl₂ N₆ O₂ S: C54.75; H 3.83; N 15.97; S 6.08. Found: C 54.28; H 3.89; N 16.02; S 5.69.

EXAMPLE 88 (1R,2R)-N-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-4- hydroxyamino(imino)methyl!phenyl!-4-methylthiazole-5-carboxamide

To a solution of Na₂ CO₃ (0.72 g, 6.77 mmol) in a mixture of H₂ O (5 mL)and THF (5 mL) was added (1R,2R)-2-(4-cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methyl-thiazole-5-carboxamide methanesulfonate (0.5 g,0.84 mmol, obtained in example 31) and hydroxylamine hydrochloride (0.29g, 4.23 mmol). The reaction mixture was stirred at room temperatureovernight, and was then concentrated and the aqueous residue extractedwith CHCl₃. The organic phase was separated, dried over Na₂ SO₄,filtered and the filtrate was concentrated to a solid. Purification byflash chromatography afforded the title compound as a pale yellow solid:mp 135°-148° C.; ¹ H NMR (300 MHz, MeOH--d₄) δ (MeOH--d₄) 8.24 (s, 1H,triazole), 8.03 (dt, J_(t) =1.6, J_(d) =8.5, 2H, arom), 7.78 (dt, J_(t)=1.6, J_(d) =8.5, 2H, arom), 7.71 (s, 1H, triazole), 7.38 (dt, J_(d)=6.5, J_(t) =8.8, 1H, arom), 6.97 (ddd, J=2.4, J=8.7, J=11.5, 1H, arom),6.84 (dt, J_(d) =2.1, J_(t) =8.0, 1H, arom), 5.00 (q, J=7, 1H, CHMe),4.99 (d, J=14.3, 1H, TrCH(H)), 4.58 (d, J=14.3, 1H, TrCH(H)), 2.74 (s,3H, thiazole-Me), 1.05 (d, J=7, 3H, MeCH); MS 496 (M⁺ -NH₂); α!^(D)=-77.2° (c 1, MeOH). Analysis calculated for C₂₄ H₂₃ F₂ N₇ O₃ S.H₂ O: C52.84; H 4.62; N 17.97; S 5.88 Found: C 53.48; H 4.61; N 17.19; S 5.34.

EXAMPLE 89 (1R,2R)-2- 4- Acetoxyamino (imino)methyl!phenyl!-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

A solution of the product obtained in example 88 (150 mg, 0.28 mmol) inCHCl₃ (10 mL) was treated with triethylamine (33 μL, 0.33 mmol) andacetyl chloride (25 μL, 0.32 mmol) at 25° C. for 18 h. Next, 10% aqueousNaHCO₃ was added and the layers were separated. The organic phase waswashed with water, dried over Na₂ SO₄, filtered, concentrated andpurified by flash chromatography to give the title compound as a whitesolid: mp 146°-147° C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 8.01 (dt, J_(t)=1.9, J_(d) =8.7, 2H, arom), 7.81 (s, 1H, triazole), 7.80 (dt, J_(t)=1.9, J_(d) =8.7, 2H, arom), 7.79 (s, 1H, triazole), 7.38 (dt, J_(d)=6.5, J_(t) =8.8, 1H, arom), 6.8-6.6 (m, 2H, arom), 6.43 (br d, J=9.5,1H, NH), 5.38 (s, 1H, OH), 5.13 (br s, 2H, NH₂), 5.05 (d, J=14.5, 1H,TrCH(H)), 4.94 (br quint, J=7, 1H, CHMe), 4.52 (d, J=14.5, 1H, TrCH(H)),2.82 (s, 3H, Me-thiazole), 2.27 (s, 3H, COMe), 1.02 (d, J=6.8, 3H,MeCH); MS 327 (N-ethylheterocycle-H₂ O, C₁₆ H₁₆ N₄ O₂ S), 284 (acylgroup-H₂ O, C₁₄ H₁₀ N₃ O₂ S), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O);α!^(D) =-103.9° (c 1, MeOH). Analysis calculated for C₂₆ H₂₅ F₂ N₇ O₄ S:C 54.83; H 4.42; N 16.76; S 5.63 Found: C 53.97; H 4.38; N 16.90; S5.23.

EXAMPLE 90 (1R,2R)-2-(4-Tert-butylphenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-tert-butylphenyl)-4-methylthiazole-5-carboxylic acid (referenceexample 43) the title compound was obtained as a white solid: mp 85°-91°C.; ¹ H NMR (300 MHz, CDCl₃) δ (TMS) 7.88 (dt, J_(t) =2, J_(d) =8.5, 2H,arom), 7.81 (s, 1H, triazole), 7.79 (s, 1H, triazole), 7.47 (dt, J_(t)=2, J_(d) =8.5, 2H, arom), 7.38 (dt, J_(d) =6.5, J_(t) =8.8, 1H, arom),6.8-6.6 (m, 2H, arom), 6.38 (br d,J=9.5, 1H, NH), 5.37 (s, 1H, OH), 5.05(d, J=14.5, 1H, TrCH(H)), 4.93 (br quint, J=7, 1H, CHMe), 4.53 (d,J=14.5, 1H, TrCH(H)), 2.81 (s, 3H, Me-thiazole), 1.35 (s, 9H, CMe₃),1.02 (d, J=6.8, 3H, MeCH); GC--MS 301 (ethylaminoacyl group, C₁₇ H₂₂ N₂OS), 258 (acyl group, C₁₅ H₁₆ NOS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O);α!^(D) =-105.9° (c 1, CHCl₃). Analysis calculated for C₂₇ H₂₉ F₂ N₅ O₂S: C 61.70; H 5.56; N 13.32; S 6.10. Found: C 61.70; H 6.20; N 12.64; S5.24.

EXAMPLE 91 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-imidazol-1-yl)propyl!-4-methylthiazole-5-carboxamide

Following a similar procedure to that described in example 1 but using2-(4-cyanophenyl)-4-methylthiazole-5-carboxylic acid (reference example24) and (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-imidazol-1-yl)-2-butanol (75 mg, 0.28 mmol, obtained following the generalprocedure described in J. Org. Chem., 1995, 60, 3000-3012) in DMF (5 mL)the title compound was obtained as a white solid: mp 126°-128° C.; ¹ HNMR (300 MHz, CDCl₃) δ (TMS) 8.05 (dt, J_(t) =2, J_(d) =8.4, 2H, arom),7.50 (dt, J_(t) =2, J_(d) =8.4, 2H, arom), 7.47 (dt, J_(d) =6.5, J_(t)=8.8, 1H, arom), 7.24 (s, 1H, imidazole), 6.84.6 (m, 2H, arom), 6.52 (brd, J=9.5, 1H, NH, 6.51 (s, 1H, imidazole), 6.32 (s, 1H, imidazole), 4.85(br quint, J=7, 1H, CHMe), 4.68 (d, J=14.5, 1H, ImCH(H)), 4.29 (d,J=14.5, 1H, ImCH(H)), 2.80 (s, 3H, Me-thiazole), 1.06 (d, J=6.8, 3H,MeCH); MS 227 (acyl group, C₁₂ H₇ N₂ OS), 223 (Im--CH₂ COHAr, C₁₁ H₉ F₂N₂ O); α!^(D) =-20.4° (c 1, CHCl₃). Analysis calculated for C₂₅ H₂₁ F₂N₅ O₂ S: C 60.84; H 4.29; N 14.19; S 6.50 Found: C 60.85; H 4.31; N13.75; S 6.18.

EXAMPLE 92 (1R,2R)-2-(4-Cyanophenyl)-N-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-carboxamide

Following a similar procedure to that described in example 29 but using(2R,3R)-3-amino-2-(2-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol(obtained as described in J. Org. Chem., 1995, 60, 3000-3012) the titlecompound was obtained as a white solid: mp 107°-114° C.; ¹ H NMR (300MHz, CDCl₃) δ (TMS) 8.07 (dt, J_(t) =1.8, J_(d) =8.6, 2H, arom), 7.79(s, 1H, triazole), 7.76 (dt, J_(t) =1.8, J_(d) =8.6, 2H, arom), 7.75 (s,1H, triazole), 7.36 (dt, J_(d) =1.6, J_(t) =7.8, 1H, arom), 7.3-7.3 (m,1H, arom), 7.1-7.0 (m, 2H, arom), 6.50 (br d, J=9.3, 1H, NH), 5.29 (d,J=1.6, 1H, OH), 5.08 (d, J=14.2, 1H, 7rCH(H)), 4.99 (br quint, J=7, 1H,CHMe), 4.52 (d, J=14.2, 1H, TrCH(H)), 2.83 (s, 3H, Me-thiazole), 1.03(d, J=6.8, 3H, MeCH); GC/MS 270 (ethylaminoacyl group, C₁₄ H₁₂ N₃ OS),227 (acyl group, C₁₂ H₇ N₂ OS), 206 (Tr--CH₂ COHAr, C₁₀ H₉ FN₃ O);α!^(D) =-115.61° (c 1, CHCl₃). Analysis calculated for C₂₄ H₂₁ FN₆ O₂S.1/2H₂ O: C 59.36; H 4.53; N 17.30; S 6.59. Found: C 59.63; H 4.73; N16.68; S 6.15.

EXAMPLE 93 (1R,2R)-N-2-(2,4Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tiazol-1-yl)propyl!-2-4fluorophenyl)4-methylthiazole-carboxamide

Following a similar procedure to that described in example 1 but using2-(4fluorophenyl) methylthiazole-5-carboxylic acid the title compoundwas obtained as a white amorphous solid: ¹ H NMR (300 MHz, CDCl₃) δ(TMS) 7.96 (m, 2H, arom), 7.81 (s, 1H, triazole), 7.79 (s, 1H,triazole), 7.37 (dt, J_(d) =65, J_(t) =8.8, 1H, arom), 7.16 (tt, J=2,J=8.5, 2H, arom), 6.8-6.6 (m, 2H, arom), 6.40 (br d, J=9.5, 1H, NH),5.41 (s, 1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)), 4.94 (br quint, J=7,1H, CHMe), 4.52 (d, J=14.5, 1H, TrCH(H)), 2.80 (s, 3H, Me-thiazole),1.02 (d, J=6.8, 3H, MeCH); MS 263 (ethylaminoacyl group, C₁₃ H₁₂ FN₂OS), 220 (acyl group, C₁₁ H₇ FNOS), 224 (Tr--CH₂ COHAr, C₁₀ H₈ F₂ N₃ O);α!^(D) =-113.5° (c 0.5, CHCl₃). Analysis calculated for C₂₃ H₂₀ F₃ N₅ O₂S: C 56.67; H 4.14; N 14.37; S 6.58 Found. C 56.87; H 4.19; N 14.00; S6.29.

EXAMPLE 94

In vitro activity

In vitro activity was evaluated against C. albicans, C. krusei, andAspergillus fumigatus by the agar dilution method. Test strains wereeither clinical isolates or were obtained from ATCC. Stock solutionscontaining 800 μg/mL were prepared by solving the test products in 50%ethanol. The culture medium used was Kimmig's agar (K. A., E. Merck)suplemented with 0.5% glycerol. Plates containing serial dilutions (80to 0.025 μg/mL) of the test products were inoculated with 10 μL of thefungal inocula, containing 10⁵ colony forming units (cfu)/mL. Plateswere incubated at 25° C. during 48 h for Canadida p. and during 5 daysfor Apergillus fumigatus. Following incubation MICs (minimal inhibitoryconcentrations) were determined. Results are shown in the followingtable:

    ______________________________________    IN VITRO ACTIVITIES (MIC in μg/mL)    EXAMPLE No.              C. albicans C. krusei   Asp. fumigatus    ______________________________________    2         0.15        2.5         10    3         0.07        5           5    8         1.15        1.25        10    10        0.63        2.5         10    15        0.15        2.5         5    19        0.15        5           2.5    22        ≦0.03                          0.63        5    23        ≦0.03                          2.5         5    24        ≦0.03                          1.25        1.25    25        ≦0.03                          1.25        1.25    26        ≦0.03                          0.63        1.25    27        0.15        1.25        0.63    28        ≦0.03                          1.25        1.25    29        ≦0.03                          2.5         2.5    34        0.07        1.25        10    39        0.07        0.63        1.25    41        ≦0.03                          1.25        2.5    43        ≦0.03                          1.25        10    51        ≦0.03                          0.31        2.5    55        ≦0.03                          0.07        0.31    57        ≦0.03                          0.63        0.63    59        ≦0.03                          0.63        5    74        0.07        1.25        5    77        ≦0.03                          1.25        2.5    87        ≦0.03                          0.63        1.25    90        0.63        1.25        1.25    92        ≦0.03                          5           2.5    ______________________________________

EXAMPLE 95

In vivo activity (systemic candidiasis)

Groups of 10 male mice were inoculated i.v. with 0.2 mL of a suspensioncontaining (2-8)×10⁷ cfu/mL of Candida albicans. Compounds wereadministered orally at 1 mg/kg at times 1, 4 and 24 h after infection.Following this protocol, animals treated with the products of examples2, 3, 4, 7,8,9,10,15,16,18,19,21,22,24,25,26,27,28,29,30,31,34,36,43,44,51,52,55,56,57,62,66,73,74,77,82,83,84,85,87 and 92 showed 100% protection on beday where all the animals in the control group had died (days 24).

EXAMPLE 96

In vivo activity (systemic aspergillosis)

According to a similar in vivo model of systemic aspergillosis in mice,animals treated with the products of examples 3, 25, 26, 29, 51, and 57(p.o. 20 mg/kg/day, 5 days) showed 60-100% protection on day 25postinfection. Mortality in the control group on day 25 was 90%.

We claim:
 1. A compound of formula I: ##STR10## as a racemate, adiastereomer mixture or as a pure enantiomer, wherein: X represents N;Arrepresents phenyl or phenyl substituted with one or more halogen and/ortrifluoromethyl groups; R₁₂ is C₁ -C₄ alkyl; R₂ is hydrogen or C₁ -C₄alkyl; or R₁ together with R₂ form a C₂ -C₄ polymethylene chain; R₃ ishydrogen, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkyl-C₁ -C₄alkyl, C₁ -C₄ haloalkyl, phenyl-C₁ -C₄ alkyl (wherein the phenyl groupcan be optionally substituted with 1, 2, 3 or 4 groups R₅, which can bethe same or different), a group --(CH₂)_(n) --CH₂ OH, a group--(CH₂).--CH₂ OBn, a group --(CH₂)_(n) --CH₂ NR₆ R₇, a group --(CH₂)_(n)--CH₂ COOR₆, or a group --(CH₂)_(n) CH₂ COOBn; R₄ is hydrogen; Arepresents phenyl, thiophene, furan, pyrrole, pyrazole, thiazole,imidazole, isothiazole, oxazole, isoxazole, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole,1,2,4-thiadiazole, or their respective hydrogenated versions, wherein Acan be unsubstituted or have 1, 2, 3 or 4 groups R₈ ; B represents aphenyl group which can be optionally substituted with 1, 2, 3 or 4groups R₉ ; R₅ represents C₁ -C₄ alkyl, C₁ -C₄ haloalkyl or halogen; nrepresents 0, 1, 2 or 3; R₆ and R₇ independently represent hydrogen orC₁ -C₄ alkyl; R₈ represents C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₁ -C₄haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy, halogen, phenyl (optionallysubstituted with a group halogen, cyano, C₁ -C₄ haloalkyl or C₁ -C₄haloalkoxy), nitro, cyano, hydroxy, hydroxymethyl, a group --NR₆ R₇, agroup --CONR₆ R₇, a group --COR₆, a group --COOR₆, or a group --SO_(z)R₁₀ ; R₉ represents C₁ -C₄ alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, C₃-C₆ cycloalkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy,2-carboxy-2-propyl, halogen, nitro, cyano, hydroxy, benzyloxy,hydroxymethyl, a group --CH₂ --OCO--R₆, a group --CO--R₆, a group--COO--R₆, a group --SO_(z) R₁₀, a group --NR₆ R₇, a group --CONR₆ R₇, agroup --C(═NR₆)NHR₁₁, a group --C(═NR₁₁)OR₆, and additionally one of thegroups R₉ can also represent 1-pyrrolyl, 1-imidazolyl,1H-1,2,4-triazol-1-yl, 5-tetrazolyl (optionally substituted with C₁ -C₄alkyl), 1-pyrrolidinyl, 4-morpholinyl, 4-morpholinyl-N-oxide, phenyl orphenoxy (both optionally substituted with a group C₁ -C₄ alkyl, C₁ -C₄haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy, halogen, nitro or cyano),or a group of formula (i)-(iv) ##STR11## R₁₀ represents C₁ -C₄ alkyl; zrepresents 0, 1 or 2; R₁₁ represents hydrogen, --CONH₂, --COMe, --CN,--SO₂ NHR₆, --SO₂ R₁₀, --OR₆, or --OCOR₆ ; R₁₂ represents hydrogen ormethyl; R₁₃ represents hydrogen, isopropyl, cyclopentyl, cyclopropyl,2-butyl, 3-pentyl, 3-hydroxy-2-butyl, or 2-hydroxy-3-pentyl; prepresents 0 or 1; R₁₄ represents halogen, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, nitro, amino, cyano, or a group of formula (i); E represents--CH₂ -- or --C(═O)--; G represents NH or O; Y represents a single bond,--S--, --SO--, --SO₂ --, --O-- or --NR₆ --; m and q independentlyrepresent 0, 1 or 2; and the salts and solvates thereof.
 2. A compoundas claimed in claim 1 wherein R₁ represents C₁ -C₄ alkyl and R₂represents hydrogen.
 3. A compound as claimed in claim 2 wherein R₁represents methyl.
 4. A compound as claimed in claim 1 R₃ representshydrogen.
 5. A compound as claimed in claim 1 wherein Ar represents2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl or4-chlorophenyl.
 6. A compound as claimed in claim 1 wherein A representsphenyl, wherein A can be unsubstituted or have 1, 2, 3 or 4 groups R₈.7. a compound as claimed in claim 1 wherein A represents thiophene,furan, pyrrole, pyrazole, thiazole, imidazole, oxazole, isoxazole,1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole or1,2,4-thiadiazole, and which can be unsubstituted or have 1 or 2 groupsR₈.
 8. A compound as claimed in claim 1 wherein the stereochemistry ofthe compounds is (R,R).
 9. A compound as claimed in claim 1 wherein:R₁represents methyl; R₂ represents hydrogen; R₃ represents hydrogen; Arrepresents 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,4-(trifluoromethyl)phenyl or 4-chlorophenyl; A represents thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,4-oxadiazole, or 1,2,4-thiadiazole, wherein A can be optionallysubstituted with one or two C₁ -C₄ alkyl or C₁ -C₄ haloalkyl groups; Brepresents a phenyl group substituted with 1 or 2 groups R₉ ; R₉represents C₁ -C₄ alkyl, C₂ -C₄ -alkenyl, C₂ -C₄ -alkynyl, C₃ -C₆cycloalkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkoxy,2-carboxy-2-propyl, halogen, nitro, cyano, hydroxy, benzyloxy,hydroxymethyl, a group --CH₂ --OCO--R₆, a group --CO--R₆, a group--COO--R₆, a group --SO_(z) R₁₀, a group --NR₆ R₇, a group --CONR₆ R₇, agroup --C(═NR₆)NHR₁₁ or a group --C(=NR₁₁)OR₆ ; Y represents a singlebond and m═q═0; and the stereochemistry of the compounds is (R,R).
 10. Acompound as claimed in claim 1 selected from:(a)(1R,2R)-1-(4-chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-methyl-1H-pyrazole-4-carboxamide; (b) (1R,2R)-1-(4-chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-5-trifluoromethyl-1H-pyrazole-4-carboxamide;(c) (1R,2R)-1-(4-chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-2-methyl-3(1H-1,2,4-tiazol-1-yl)propyl!-3,5dimethyl-1H-pyrazole-4-carboxamide;(d) (1R ,2R)-N- 2-(2,4difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4triazol-1-yl)propyl!-4-methyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxamide;(e) (1R,2R)-2-(4-chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide;(f) (1R,2R)-N- 2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-4-methyl-2-(4-trifluoromethoxyphenyl)thiazole-5-carboxamide;(g) (1R, 2R)-2-(4 cyanophenyl)-N- 2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3(1H-1,2,4-triazol-1-yl)propyl!-4-methylthiazole-5-carboxamide;(h) (1R,2R)-5-(4-chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!thiophene-2-carboxamide;(i) (1R, 2R,)-5-(4chlorophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4triazol-1-yl)propyl!-3-methylthiophene-2-carboxamide;(j) (1R,2R)-5-(4cyanophenyl)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-3-methylthiophene-2-carboxamide;(k) (1R,2R)-2-(4-cyanophenyl)-N-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4triazol-1-yl)propyl!-methylthiazole-5-carboxamide;(l) (1R,2R)-N-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl!-2-(4fluorophenyl)-4-methylthiazole-5-carboxamide;or a salt or solvate thereof.
 11. A process for preparing a compound offormula I as defined in claim 1, which comprises:(a) reacting a compoundof formula II ##STR12## wherein X, R₁, R₂, R₃, R₄ and Ar are as definedin claim 1, with an acid of formula III ##STR13## wherein A, B, Y, m andq are as defined in claim 1, in the presence of a condensing agent, orwith a reactive derivative of said acid III in the presence of a protonscavenger base; or (b) converting in one or a plurality of steps acompound of formula I into another compound of formula I; and (c) ifdesired, after steps (a) or (b), reacting a compound of formula I withan acid to give the corresponding acid addition salt.
 12. The processaccording to claim 11, wherein the reactive derivative of said acid IIIis an acid chloride, an anhydride or a mixed anhydride.
 13. Apharmaceutical composition which comprises an effective amount of acompound of formula I as claimed in claim 1 or a pharmaceuticallyacceptable salt or solvate thereof in admixture with one or morepharmaceutically acceptable excipients.
 14. An agrochemical compositionwhich comprises a compound of formula I as claimed in claim 1 or a saltor solvate thereof in admixture with one or more agrochemicallyacceptable excipients.
 15. A method for the treatment or prevention of afungal infection in an animal, said method comprising administering acompound of formula I as claimed in claim 1 or a pharmaceuticallyacceptable salt or solvate thereof to an animal in need of suchtreatment or prevention.
 16. The method of claim 15, wherein said animalis a human.
 17. A method for the treatment or prevention of a fungalinfection in a plant, said method comprising applying a compound offormula I as claimed in claim 1, or a salt or solvate thereof to a plantin need of such treatment or prevention.
 18. A compound as claimed inclaim 1 wherein:A represents phenyl, thiophene, furan, pyrrole,pyrazole, thiazole, imidazole, isothiazole, oxazole or isoxazole,optionally substituted with 1, 2, 3 or 4 groups R₈.
 19. A compound asclaimed in claim 1 whereinA represents phenyl, thiophene, furan,pyrrole, pyrazole, thiazole, imidazole, isothiazole, oxazole, isoxazole,1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole,1,2,4-thiadiazole, pyrroline, imidazoline or pyrazoline, optionallysubstituted with 1, 2, 3 or 4 groups R₈.